高度脂溶性钙离子拮抗剂 在高血压、动脉硬化中的应用

北京大学人民医院 孙宁玲

高血压的进展高血压的进展2000全球死亡率: 高血压对其他危险因素的影响

高死亡率 , 发展中地区低死亡率 发展中地区发达地区

高血压 (BP)

吸烟高胆固醇

低体重性别为男性高体重指数

少动生活方式饮酒

室内环境污染缺铁

0 1000 2000 3000 4000 5000 6000 7000 8000死亡率分布

(In thousands; total 55,861,000)Adapted from Ezzati et al, Lancet, 2002.

高血压患者心血管事件危险性增高高血压患者心血管事件危险性增高 弗明翰心脏研究 弗明翰心脏研究 - - 高血压与正常血压的心血管事件危险性高血压与正常血压的心血管事件危险性

(( 患者年龄患者年龄 35-6435-64 岁，随 访岁，随 访 3636 年年 ))

9.5

3.3 2.45

2 3.5 2.1

45.4

21.3

12.4

6.29.9

7.3

13.9

6.3

22.7

0

10

20

30

40

50

男 女 男 女 男 女 男 女

正常血压高血压

Risk RatioRisk Ratio 2.02.0 2.22.2 3.83.8 2.62.6 2.02.0 3.73.7 4.04.0 3.03.0

Excess RiskExcess Risk 22.722.7 11.811.8 9.19.1 3.83.8 4.94.9 5.35.3 10.410.4 4.24.2

冠脉疾病冠脉疾病 中风中风 外周血管疾病外周血管疾病 心衰心衰

Bie

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Rat

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Bie

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Ag

e-A

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sted

Rat

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100

010

00

Kannel WB JAMA 1996;275(24):1571-1576.Kannel WB JAMA 1996;275(24):1571-1576.

高血压及动脉硬化 参与 心血管事件的发生

高血压与动脉硬化是相联的高血压与动脉硬化是相联的

Hypertension

Other factors- hypercholesterolaemia- glucose intolerance etc.

Atherosclerosis

Coagulation factors

Clinical events of CHD- angina- infarction- sudden death

(very late stage)

Relationship between hypertension, Relationship between hypertension, atherosclerosis and cardiovascular eventsatherosclerosis and cardiovascular events

Hypertension

出血性卒中

Atherosclerosis

缺血性卒中

其他致动脉硬化因素

血栓

心绞痛 /心肌梗死

高血压是动脉硬化的启动因素

动脉粥样硬化的进展过程与高血压有关动脉粥样硬化的进展过程与高血压有关

LDL

Oxidised LDL

动脉壁损伤细胞粘附于内皮表面 内皮功能失调

使内皮渗透性增加

生长因子eg. PDGF, FGF, TGF-

平滑肌细胞增殖

高血压高血压

高血压

高血压怎样导致动脉硬化：高血压怎样导致动脉硬化： ‘‘ haemodynamic’ factorshaemodynamic’ factors

Internal Carotid

External Carotid

Flow Divider

Common Carotid Artery

Main steps in the atherosclerotic Main steps in the atherosclerotic process (atherogenesis)process (atherogenesis)

平滑肌细胞增殖 ...

迁移至内皮下

高血压

高血压怎样导致动脉硬化高血压怎样导致动脉硬化 :: ‘mechanical’ factors ‘mechanical’ factors

内皮损伤

High BP Lipids/free radicals

渗透性增加 内皮的收缩因子 ( 内皮素 ) 占优

Main steps in the atherosclerotic Main steps in the atherosclerotic process (atherogenesis)process (atherogenesis)

(Per-) Oxidation

吞噬细胞增殖

Esterification

（脂化作用）

炎症与动脉粥样硬化形成及演变炎症与动脉粥样硬化形成及演变

正常 黏附 侵润 剥落

内皮细胞

平滑肌细胞

单核细胞

CAMs

基质

泡沫细胞

细胞因子生长因子

T 淋巴细胞

激活的巨核细胞

组织因子组织因子

栓塞栓塞

MMPsMMPs

基质降解基质降解

高血压

L-NMMA = NL-NMMA = NGG monomethyl L-arginine monoacetate. monomethyl L-arginine monoacetate.

John and Schmieder. John and Schmieder. J HypertensJ Hypertens. 2000;18:363-374.. 2000;18:363-374.

Gene Gene expressionexpression

GGGG

Endothelial CellEndothelial Cell

L-ArginineL-ArginineL-NMMAL-NMMA

eNOSeNOSCaCa2+2+ calmodulin

calmodulin

AcetylcholineAcetylcholine

Substance PSubstance P

BradykininBradykinin

22--agonistsagonistspathwaypathway

L-ArginineL-Arginine

NONO

Soluble guanylate Soluble guanylate cyclasecyclase cGMPcGMP

Endothelium-dependent Endothelium-dependent vasodilationvasodilation

Smooth Muscle Cell

Endothelium-Dependent Vasodilation: Endothelium-Dependent Vasodilation:

L-Arginine–Nitric Oxide PathwayL-Arginine–Nitric Oxide Pathway

Endothelial injury

Removal of endothelial cells

Cytokines and growth factors

Cell adhesion molecules

Endothelial repair

Incorporation of endothelial

progenitor cells

Cytokines and growth factors

Cell adhesion molecules

Adapted from Omoigui and Dzau. J Vasc Med Biol. 1991;3:382-391.

高血压是内皮功能高血压是内皮功能不良的重要原因不良的重要原因并导致血管组织并导致血管组织

结构的病变结构的病变

Abnormal EndotheliumAbnormal Endothelium

Vasocon-Vasocon-strictionstriction

Platelet/Platelet/leukocyteleukocyteadhesionadhesion

SMCSMCmigrationmigrationandandgrowthgrowth

LipidLipiddepositiondepositionClearanceClearance

高血压高血压 糖尿病糖尿病

DysfunctionDysfunction

血脂紊乱

既往研究发现：

积极降脂治疗可以改善内皮 功能，降低预后事件

Effects of Lipid-Lowering Therapy Effects of Lipid-Lowering Therapy on Endothelial Function in CHD on Endothelial Function in CHD

PatientsPatients

Treasure et al. Treasure et al. N Engl J MedN Engl J Med. 1995;332:481-487.. 1995;332:481-487.

Ch

an

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iam

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r (%

)C

ha

ng

e in

Dia

me

ter

(%)

30

20

10

0

-10

-20

-30

-40

-50InitialInitial Follow-upFollow-up

Placebo Group

InitialInitial Follow-upFollow-up

Lovastatin Group

DilationDilation

ConstrictionConstriction

Acetylcholine ChallengeAcetylcholine Challenge

Effect of Aggressive Lipid Lowering on Carotid IMT in Effect of Aggressive Lipid Lowering on Carotid IMT in Heterozygous Familial Hypercholesterolemia: ASAPHeterozygous Familial Hypercholesterolemia: ASAP

Smilde et al. Smilde et al. LancetLancet. 2001;357:577-581.. 2001;357:577-581.

Ch

an

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in IM

T (

mm

)C

ha

ng

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IMT

(m

m)

0.090.09

0.070.07

0.050.05

0.030.03

0.010.01

-0.01-0.01

-0.03-0.03

-0.05-0.05

-0.07-0.07

-0.09-0.0900 11 22

Atorvastatin 80 mg (n=160)Atorvastatin 80 mg (n=160)

YearsYears

Baseline LDLBaseline LDL

8.33 8.33 mmol/Lmmol/L

Overview of Statin Overview of Statin TrialsTrials

-40

-20

0

AF/TexCAPSAF/TexCAPS 6605 6605 -24% -24%

44S S 4444 4444 -35%-35%

LIPID LIPID 9014 9014 -25%-25%

CARECARE4159 4159 -28%-28%

WOS WOS 6595 6595 -20%-20%

Trial Trial N N

LDLLDL

% % Reduction Major Coronary EventsReduction Major Coronary Events

SecondarySecondary PrimaryPrimary

**PP<.001; <.001; ††PP=.002=.002

LaRosa et al. LaRosa et al. JAMAJAMA. 1999;282:2340-2346.. 1999;282:2340-2346.

-38*

-25* -25††

-31*

-38*

结 论结 论

积极的降脂治疗可以改善内皮功能

积极的降脂治疗可以改善动脉硬化及中间终点

积极降脂治疗可以改善预后终点

降压治疗是否可以改善预后？

降压治疗是否有改善内皮功能的作用？

什么样降压药物具有较好的抗动脉硬化效果？

问题的提出：

Reduction of events with Reduction of events with antihypertensive therapy antihypertensive therapy

20-25%35-45%

Antihypertensive therapy

CHF Stroke MI

-20

-0

-40

-60

>50%

2003 JNC7

钙离子在高血压及动脉硬化中钙离子在高血压及动脉硬化中的作用的作用

Ca++

Calciumions

1) 内皮细胞 ( 内皮素 )

2)血管平滑肌细胞

3)巨噬 / 泡沫细胞

4)LDL/ 胆固醇代谢

钙离子拮抗剂是否能过阻断这些过程？

降压治疗（ CCB ）是否可以改善预后

降压治疗（ CCB) 是否有改善内皮功能的作用？

什么样降压药物具有较好的抗动脉硬化效果？

回答提出的问题

CCBsCCBs 在动脉硬化中的临床试验 在动脉硬化中的临床试验

Trial n Drug

regimen

Patient group

Outcome

INTACT 425 Nifedipine vs placebo

Mild CAD 28% new lesions

REGRESS 885 Pravastatin vs placebo

Atherosclerosis

(males)

50% new lesions with concomitant CCB

PREVENT 825 Amlodipine vs placebo

CAD 0.0126mm IMT (amlodipine)

0.033mm IMT (placebo)

J-MIC (B) 210 Nifedipine vs ACE inhibitor

HT and CAD Nifedipine significantly better for preventing lesion progression

Jukema J, et al. Arterioscler Thromb Vasc Biol 1996;16:425–30. Lichtlen P, et al. Lancet 1990;335:1109–13.Pitt B, et al. Circulation 2000;102:1503–10.

结果已经发表在 11 月 8 日的

Lancet 2003， 362： 1527-35.

• 荟萃 29 个随机试验• 162,341 例患者• 700,000 余次的病人年

降压治疗试验协作研究组 （ ABPL ）第二轮分析

ABPL 试验（血压的差异与事件的关系） 活性药物 vs plac

mmHg 差异 ACEI / plac ( -5 / -2 ) CCB / plac ( - 8 / - 4 )

R R R R

总死亡率 0.80 0.89 CVD死亡 0.80 0.78

CVD事件 0.72 0.82 脑卒中 0.72 0.62

冠心病 0.80 0.78

心力衰竭 0.82 1.21

ABPL 试验（血压的差异与事件的关系） 活性药物 vs 活性药物

mmHg 差异 ACEI CCB ACEI

D / BB (+ / 0 ) D/BB (+1/ 0 ) CCB (+1 / +1 )

R R R R R R 总死亡率 1.00 0.99 1.04 CVD死亡 1.03 1.05 1.03

CVD事件 1.02 1.04 0.97 脑卒中 1.09 0.93 1.12

冠心病 0.98 1.01 0.96

心力衰竭 1.07 1.33 0.82

卒 中不同活性药的比较

随机治疗

ACEI vs D/BB

CA vs D/BB

ACEI vs CA

试验数

6

9

6

病例数

47449

68467

25767

BP

(mmHg)

0/2

0/0

1/1

0.5 1.0 2.0

RR (95% CI)

1.09(1.00, 1.18

0.93(0.86, 1.01

1.12(1.01, 1.25

Relative Risk

前者更好 后者更好

第二轮分析 ABPL

降压治疗（ CCB) 是否可以改善预后？

降压治疗（ CCB ）能够改善内皮功能

什么样降压药物具有较好的抗动脉硬化效果？

回答提出的问题

Circulating endothelial progenitor Circulating endothelial progenitor cells cells

are derived from bone marroware derived from bone marrow

EPC: endothelial progenitor cell

EPC

Smooth muscle

Endothelium

Coronary arteryBone marrow

EPCmigration

EPCBone marrow

EPCincorporation

EPC: endothelial progenitor cell

心血管危险因素是与内皮原细胞数量心血管危险因素是与内皮原细胞数量的减少及不同有关的减少及不同有关

En

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(co

lon

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g u

nit

s)

–5 0 5 10 15

Framingham risk score

0

20

40

60

30

50

70

10

20

p=0.001, r= –0.47

Hill J et al. N Engl J Med 2003

内皮功能改善与内皮源性细胞数量加内皮功能改善与内皮源性细胞数量加有关有关

En

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(co

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0 2 4 6 8

Change in brachial reactivity (%)

0

20

40

60

30

50

70

10

1610 12 14

Hill J et al. N Engl J Med 2003

p=0.001, r= –0.59

EPC: endothelial progenitor cell

TREND: Endothelial Function TREND: Endothelial Function

and ACE Inhibitionand ACE Inhibition

**PP<.0003 for quinapril vs placebo.<.0003 for quinapril vs placebo.

Mancini et al. Mancini et al. CirculationCirculation. 1996;94:258-265.. 1996;94:258-265.

-4-2024

68

101214

PP=.002 overall=.002 overallN

et

Ch

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%)

in T

arg

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me

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Ne

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(%

) in

Ta

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po

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6 M

on

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Re

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on

se

Aft

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Mo

nth

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Acetylcholine Dose (mol/L)Acetylcholine Dose (mol/L)

1010-6-6

1010-4-4

**PlaceboPlacebo

QuinaprilQuinapril

**

NO Production From Human NO Production From Human Coronary Microvessels: Amlodipine and Coronary Microvessels: Amlodipine and

RamiprilatRamiprilat

Zhang et al. Zhang et al. Am J CardiolAm J Cardiol. 1999;84:27L-33L.. 1999;84:27L-33L.

Ch

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Ch

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pm

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g)

Concentration (log)Concentration (log)

100

75

50

25

0

AmlodipineAmlodipine

**

**** **

**

-10 M -9 M -8 M -7 M -6 M -5 M

**

**

RamiprilatRamiprilat

**PP<.01 vs control<.01 vs control

Brovkovych V et al. Hypertension 2001

Nifedipine preserves NO concentration Nifedipine preserves NO concentration – – stimulates NO releasestimulates NO release

Electrochemical sensor

0.01 0.1 1 10 100 1,000

240

120

40

0

80

200

160

NO

rel

ease

(n

mo

l/L

)

Nifedipine (nmol/L)

Loke et al. Loke et al. Hypertension.Hypertension. 1999;34:563-567; Zhang et al. 1999;34:563-567; Zhang et al. J Pharmacol Exp Ther.J Pharmacol Exp Ther. 1999;288:742-751; 1999;288:742-751;

Laufs et al. Laufs et al. Circulation.Circulation. 1998;97:1129-1135. 1998;97:1129-1135.

Postulated Effects of Different Agents on Postulated Effects of Different Agents on Endothelial Cell NO Production Endothelial Cell NO Production

Endothelial CellEndothelial Cell

StatinsStatinsStatinsStatins

KininsKinins Inactive peptidesInactive peptides

CCBCCBCCBCCB

eNOSeNOS

NONO22ACEACEACEACE

L-ArginineL-Arginine NO + L-CitrullineNO + L-Citrulline

BKBK22

eNOS mRNAeNOS mRNA

ACEIACEIACEIACEI

不同药物对内皮功能不良的治疗作用不同药物对内皮功能不良的治疗作用

ACE-Is ARBs CCBs

动脉

coronary ++ ++no data

peripheral ++ +–

皮下微循环 ++ +++

肌性微循环

acetylcholine, metacholine

bradykinin

– – ++

++ ++no data

ACE-I: angiotension-converting enzyme inhibitor, ARB: angiotensin II receptor blocker, CCB: calcium channel blocker

降压治疗（ CCB) 是否可以改善预后？

降压治疗（ CCB) 是否有改善内皮功能的作用？

CCB 具有较好的抗动脉硬化效果

回答提出的问题

ESC/ESHESC/ESH 建议建议分析心血管事件终点分析心血管事件终点

既要看终末终点又要分析中间终点（替代终点）既要看终末终点又要分析中间终点（替代终点）

危险因素阶段 靶器官损害阶段

临床疾病阶段 终末疾病阶段

高血压糖尿病其它危险因素

颈动脉中内膜增厚冠状动脉病变血管内皮功能紊乱左室肥厚蛋白尿

心绞痛心肌梗塞脑卒中肾脏损害

心力衰竭肾功能衰竭卒中后功能障碍死亡

中间终点

逆转中间终点的目的是减少终末终点发生

心肌梗塞或中风与颈动脉厚度的关系 心肌梗塞或中风与颈动脉厚度的关系

0

5

10

15

20

25

30

35

40

45

1 2 3 4 5内膜 -中层厚度的五分位数

(combined measure of max CCA and ICA)

每10

00名病人

出现心梗或中风的比率

-年

13.6

18.4

22.2

40.9

New England Journal of Medicine, 1999;340:14-22

7.8

SECURE: Progression Slope SECURE: Progression Slope of Mean Maximum IMTof Mean Maximum IMT

0.00

0.01

0.02

0.03

Pro

gre

ssio

n M

ea

n M

ax

IMT

P

rog

ress

ion

Me

an

Ma

x IM

T

Slo

pe

(m

m/y

)S

lop

e (

mm

/y)

0.0220.022

0.0180.018

Placebo Placebo (n=227)(n=227)

Ramipril Ramipril 2.5 mg/d 2.5 mg/d

(n=232) (n=232)

0.0140.014

Ramipril Ramipril 10 mg/d 10 mg/d (n=234)(n=234)

37% 37% Relative ReductionRelative ReductionP=P=.028 vs Plac.028 vs Plac

Effect of Ramipril Was Significant After Adjustment for BP and Hx HypertensionLonn et al. Lonn et al. CirculationCirculation. 2001;103:919-925.. 2001;103:919-925.

-0.02

-0.01

0

0.01

0.02

0.03

0.04

PREVENTPREVENT ：：氨氯地平氨氯地平 显著延缓显著延缓颈动脉粥样硬化颈动脉粥样硬化

内膜中层厚度变

化

(mm)

氨氯地平氨氯地平 安慰剂

0.033

0.013

Pitt et al. Pitt et al. CirculationCirculation. 2000. . 2000.

P=0.007

INSIGHT – impact on intima-media thickness

Simon A, et al. Circulation 2001;103:2949–54.

Follow-up (years)

Ch

ang

e fr

om

bas

elin

e in

car

oti

d a

rter

y IM

T (

mm

)

Nifedipine GITS

0.04

0.03

0.02

0.01

0

–0.01

Co-amilozideProgression

Regression

p=0.007 p=0.001 p=0.006

Baseline 2 3 4

Verapamil in Hypertension and Atherosclerosis Study (VHAS)

Correlation of rate of change in mean maximum intima-media thickness (Mmax) and initial Mmax

Modified from Zanchetti A, et al. J Hypertens 1998;16:1667–76.

0.06

0.04

0.02

0

–0.02

–0.04

–0.06

–0.08

–0.10

–0.12

Rat

e o

f M

max

ch

ang

e (m

m/y

ear)

y = –0.037x + 0.051

y = –0.082x + 0.086

Verapamil

Chlorthalidone

0.5 1.0 1.5 2.0Initial Mmax (mm)

拉西地平与阿替洛尔比较拉西地平与阿替洛尔比较主要终点结果主要终点结果

((每年每年 CBMmax CBMmax 的进的进展展 ))

0.0146 0.0145

0.0057

0.0087

0

0.005

0.01

0.015

0.02

0.025

PP PP2

人群

mm

阿替洛尔 拉西地平

-61%-40%

p=0,0010 p=0,0073

Circulation.2002;19:2422-2427

ELSAELSA 研究 研究

拉西地平和细胞膜和钙通道的相互作用拉西地平和细胞膜和钙通道的相互作用

High lipophilicity Extracellular

Lacidipine

Ca2+

Intracellularslow dissociation

accumulation withinlipid bilayer

long duration of action

INTERACTION OF LACIDIPINE

WITH THE DIHYDROPYRIDINE RECEPTORS

Lacidipine inhibits the development of Lacidipine inhibits the development of atherosclerosisatherosclerosis

LDL

Oxidised LDL

动脉壁损伤后细胞粘附于内皮表面

拉西地平减少内皮功能失常和渗透性增加

拉西地平减少平滑肌细胞增殖

拉西地平减少 LDL 的氧化

Growth factorseg. PDGF, FGF, TGF-

The effect of lacidipine on endothelium-dependent The effect of lacidipine on endothelium-dependent vasodilatation in hypertensivesvasodilatation in hypertensives

700

600

500

400

300

200

100

0Bradykinin Acetylcholine

***

Normotensives

Hypertensives

Lacidipine-treated hypertensives

前壁血流增加 (%)

* p < 0.05 ** p < 0.01 compared to baseline Ghiadoni et al, 1996

拉西地平能降低拉西地平能降低 TNF-aTNF-a 刺激内皮细胞粘附分子的表达 刺激内皮细胞粘附分子的表达

Journal of Hypertension, 1999;17:1837-1841

细胞粘附分子表达的减少

(%)

氨氯地平拉西地平 乐卡地平0

-10

-20

-30

-40

-50

-60

-70

-80

-90

ICAM-1

VCAM-1

E-selectin

拉西地平抑制平滑肌细胞增殖和胆固醇脂化拉西地平抑制平滑肌细胞增殖和胆固醇脂化剂型 胆固醇的 dose 增殖效果 研究

脂化作用 (m)

Lacidipine 10-6 Inhibition Mason (1992)

Reduction (> 95%) 1-20 Inhibition Bernini (1993)

Nifedipine Reduction Etingin, Hajjar (1985), and Schmitz (1988)

Increase Daugherty (1987)No effect 10-50 Inhibition Bernini (1991, 1993)

Verapamil Reduction Daugherty (1987)Reduction (91%) 50 Inhibition Bernini (1993)

Diltiazem Reduction Daugherty (1987)

Reichardt, 1995

拉西地平治疗拉西地平治疗 5252周对高血压患者周对高血压患者血清超氧化物歧化酶血清超氧化物歧化酶 (SOD)(SOD) 活性的影响活性的影响

Yamakado, 1994

Before lacidipine

0

1

2

4

5

3

Serumsuperoxide dismutase

activity(U/ml)

After lacidipine

*

* p < 0.05

短效及长效 CCB对血压的影响Optimal therapeutic range

0 4 8 12 16 20 0 4 8 12 16 20 0

mmHg

-30

-20

-10

0

Day 27 Day 28

Short-acting drug

Long-acting drug

Early morning blood pressure

surge

凌晨血压增高的风险凌晨血压增高的风险

6:000:00 12:0018:00

Muller et al. N Engl J Med 1985;313:1315–1322Marler et al. Stroke 1989;20:473–476

0

20

40

60

80

100

120

140

160

180

脑血

管事

件 (

per

2 h

)

0

5

10

15

20

25

30

35

40

45

50

心肌

梗死

(p

er h

)

Stroke (n=1,167)Myocardial infarction (n=2,999)

Time of day

钙离子拮抗剂的钙离子拮抗剂的 T/PT/P值值

药物 T/P 值 SBP T/P 值 DBP T/P 值 平均 T/P 值

硝苯地平控释片 101.8 88.2 95.0

非洛地平 75 68 71.5

氨氯地平 68 67 67.5

缓释地尔硫卓 74 67 70.5

拉西地平治疗后血压峰值和谷值的变化拉西地平治疗后血压峰值和谷值的变化

Peak

Trough

Systolicbloodpressure(mmHg)

Diastolicblood pressure(mmHg)

55% 84% 98% 78%

0

-5

-10

-15-20-25

Placebo 1mg 2mg 4mg 6mg

63% 79% 89% 94%

0

-5

-10

-15-20-25

Meredith, 1997

Lacidipine Lacidipine 降低了高血压患者血压变异性降低了高血压患者血压变异性SBP

DBP

Variability

mmHg

Placebo

Lacidipine

151311

970

15

Baseline Treatment

mmHg

Palatini et al, 1991

Baseline Treatment

13

11

9

7

0

拉西地平长期治疗后拉西地平长期治疗后动脉顺应性明显改善动脉顺应性明显改善

Pancera, 1989

Baseline

Compliance(dyne-1cm410-7)

3

1 month 6 months

*

* p < 0.005 vs baseline

2.5

2

1.5

1

0.5

0

钙拮抗剂 - 二氢吡啶类适应证 禁忌证 强制性 可能的老年人 （无） 快速心律失常单纯收缩期高血压 充血性心力衰竭心绞痛周围血管病颈动脉粥样硬化妊娠

2003 2003 ESC/ESH ESC/ESH 药物的适应证药物的适应证 //禁忌证禁忌证

Investigator assessment of Investigator assessment of lacidipine efficacylacidipine efficacy

Tcherdakoff, 1995

Very good Good Moderate Bad

44% 2%

All patients

43%

46% 11%1%

42%

Patients 65 years

11%

Investigator assessment of lacidipine Investigator assessment of lacidipine tolerabilitytolerability

Tcherdakoff, 1995

37%

All patients

58%

38%6%

56%

Patients 65 years

5%

Very good Good Moderate

乐卡地平治疗老年乐卡地平治疗老年高血压患者的耐受性高血压患者的耐受性

THE COHORT STUDY

September 2001

研究人群研究人群COHORT

0-8 months

6-12 months*

12-18 months*

18-24 months*

Safety/ITT populationn = 828

氨氯地平n = 200

n = 118

n = 70

n = 30

拉西地平n = 208

n = 134

n = 84

n = 45

乐卡地平n = 420

n = 276

n = 169

n = 78

Adjusted mean change from baselineAdjusted mean change from baseline(ITT 6 months)(ITT 6 months)COHORT

Supine SBP

-35

-30

-25

-20

-15

-10

-5

0

Supine DBP

-35

-30

-25

-20

-15

-10

-5

0

LercanidipineAmlodipineLacidipine

ANCOVA: NSMean SE

ADVERSE EVENTS SPONTANEOUSLY REPORTEDADVERSE EVENTS SPONTANEOUSLY REPORTEDOR DETECTED BY THE INVESTIGATOROR DETECTED BY THE INVESTIGATOR

(% of patients with AE typical of CCB)(% of patients with AE typical of CCB) COHORT

0

5

10

15

20

水肿 头晕 眩晕 脸潮红 头痛 心悸 心动过速

Lercanidipine

Amlodipine

Lacidipine

P<0.0001%

% % PTS WITH EDEMA PTS WITH EDEMA (up to 6 months)(up to 6 months)COHORT

0

5

10

15

20

25

30

35

40

45

50

水肿 红肿 体重增加

LercanidipineAmlodipineLacidipine

X2 (P):

%

<0.0001 <0.0001 <0.0008

症状

ESC/ESH 2003ESC/ESH 2003抗高血压药物的选择抗高血压药物的选择

抗高血压治疗的获益并非来源于所用的降压药物，而主要是取决于血压降低本身

但亦有证据表明，不同类别的抗高血压药物具有特别的临床益处

钙拮抗剂－颈动脉粥样硬化

Endothelial progenitor

cells

Anti-inflammatoryDecreased leukocyteadhesion

Reduced permeability

Increased NO availability

Effects of Lacidipine

REDUCED RISK OF A CV EVENT

DECREASEDBLOOD

PRESSURE

乐息平对内皮功能不良和器官损害过程的纠正

单核细胞

损伤的内皮

巨噬细胞 泡沫细胞

脂质

血小板

斑块

氧化应激1

2

3

CCBCCB 的抗动脉粥样硬化过程的抗动脉粥样硬化过程– 斑块形– 斑块形成的不同阶段成的不同阶段

平滑肌细胞 4

Emerging Drugs 1998; 3:135-145

5

谢 谢