MANAGEMENT OF CORONARY ARTERY DISEASE AND HEART FAILURE FOR CURING EVEN STROKE PREVENTION

The cardiovascular continuum of events

Myocardial Ischemia

CAD

plaque
Atherosclerosis

Risk Factors ( DYSLIPIDEMIA , BP, DM, Insulin Resistance, Platelets, Fibrinogen, etc)

Adapted from Dzau et al. Am Heart J. 1991;121:1244-1263

The cardiovascular continuum of events

Coronary Thrombosis Myocardial Ischemia

CAD

Atherosclerosis

Risk Factors ( DYSLIPIDEMIA , BP, DM, Insulin Resistance, Platelets, Fibrinogen, etc)

Adapted from Dzau et al. Am Heart J. 1991;121:1244-1263

Penyumbatan pembuluh darah

Pembuluh darah normal

Al ir a Pembuluh n darah darah

Plak akibat kolesterol Yang menempel pada dinding pembuluh

kolesterol

Plak

Pembuluh darah dengan kadar kolesterol tinggi

Otak yang terkena stroke

Penyumbatan karena plak

Arteri

The cardiovascular continuum of events

ACS Coronary Thrombosis Myocardial Ischemia

CAD

Atherosclerosis

Risk Factors ( DYSLIPIDEMIA , BP, DM, Insulin Resistance, Platelets, Fibrinogen, etc)

Adapted from Dzau et al. Am Heart J. 1991;121:1244-1263

The cardiovascular continuum of events

ACS Secondary prevention Coronary Thrombosis Arrhythmia and Loss of Muscle

Myocardial Ischemia

Remodeling

CAD

Ventricular Dilatation Congestive Heart Failure End-stage Heart Disease

Adapted from Dzau et al. Am Heart J. 1991;121:1244-1263

Atherosclerosis

Primary prevention

Risk Factors ( Dyslipidemia, BP, DM, Insulin Resistance, Platelets, Fibrinogen, etc)

Levels of Risk Associated with Smoking, Hypertension and Hypercholesterolemia

Hypertension
x3
x4.5

x9 x16

x1.6

Smoking

x6

x4

Dyslipidemia

(Adapted from Poulter et al., 1993)

JNC VII: Classification of blood pressure

Blood pressure classification Normal Prehypertension Stage 1 hypertension Stage 2 hypertension Systolic BP (mm Hg) <120 120-139 140-159 >160 or or Diastolic BP (mm Hg) <80 80-89 90-99 >100

or
or

The JNC VII. JAMA 2003;289:2560-72

INDICATIONS FOR INDIVIDUAL DRUG CLASSES

Diuretic blocker Heart failure Post-MI High coronary disease risk Diabetes Chronic kidney disease Stroke prevention ACE inhibitor ARB CCB Aldoantagonist

The JNC VII Report. JAMA 2003;289:2560-2572

MOST

PATIENTS

NEED

TWO

OR

MORE

ANTIHYPERTENSIVE AGENTS TO CONTROL

THEIR BLOOD PRESSURE

Possible combinations of antihypertensive agents

Diuretics

-blockers

ACs

-blockers

CCBs

ACE inhibitors
2003 ESH/ESC guidelines for the management of arterial hypertension

Possible combinations of antihypertensive agents

Diuretics

-blockers

ACs

-blockers

CCBs

ACE inhibitors
2003 ESH/ESC guidelines for the management of arterial hypertension

NCEP Classification of Blood Lipid Values In Adults

Lipid Value (mg/dl)
<100 100-129 130-159 160-189 190 <200 200-239 240

Classification
Optimal Near or above optimal Borderline high High Very high Desirable Borderline high High

LDL-C

TC

HDL-C

<40 60
<150 150-199 200-499 500

Low (increased risk) High (cardioprotective)

Normal Borderline high High Very high

TG

NCEP-ATP III guidelines. JAMA 2001;285:2486-2497

NCEP-ATP III: TARGET OF TREATMENT

ELEVATED LDL CHOLESTEROL

METABOLIC SYNDROME

NCEP-ATP III. JAMA 2001;285:2486-2497

Pleiotropic effects of a drug are actions other than those for which the agents was specifically developed. as side It may be or

undesireble

(such

effects

toxicity), neutral, or, as is especially the case with statin, beneficial.

Davignon J. Circulation 2004;109[suppl III]:III-39III-43

PLANTS RESOURCE FOR PREVENTION EVEN FOR CURING STROKE

Allii Sativi Bulbus (Garlic)

Clasification Kingdom : Plantae Division : Spermatophyta Subdivision : Angiospermae Class : Monocotyledonae Ordo : Liliales Famili : Liliaceae Genus : Alium Spesies : Allium sativum Linn

Description 1. 30-60 cm tall, 2. strong smelling when crushed. 3. The underground portion consists of a compound bulb with numerous fibrous rootlets; 4. the bulb gives rise above ground to a number of narrow, keeled, grasslike leaves. 5. The leaf blade is linear, flat, solid, 1.0-2.5cm wide, 30-60 cm long, and has an acute apex. 6. Leaf sheaths form a pseudostem. Inflorescences are umbellate; scape smooth, round, solid, and coiled at first, subtended by membraneous, long-beaked spathe, splitting on one side and remaining attached to umbel. 7. flowers are variable in number and sometimes absent, seldom open and may wither in bud. 8. Flowers are on slender pedicels; consisting of perianth of 6 segments, about 4-6mm long, pinkish; stamens 6, anthers excerted; ovary superior, 3-locular. 9. Fruit is a small loculicidal capsule.

STRUCTURE AND SUBSTANCE

Allicin

Alliin

PHARMACOLOGY
1. In-vivo (dog, rabbit, mice) causing decreasing blood presure
2. Reducing vascular resistension with smooth muscle relaxation 3. Changes of potential membraneHyperpolarizationKalium chanel open frequentlyCa Chanel closedVasodilatation 4. Active substance of this effect is unknow

5. Increasing NO synthesisdecreasing blood presure

PHARMACOLOGY ANTIPLATELET AGGREGATION

IN THE ACTIVATING EFFECT OF GARLIC ON FIBRINOLYSIS AND ITS INHIBITORY EFFECT ON PLATELET AGGREGATION HAVE BEEN DEMONSTRATED IN TOTAL 16 EXPERIMENTAL STUDIES, IN VITRO AND VIVO. THE STUDIED SHOWED THAT THE GARLIC ACT TO STIMULATE ANDOGENOUS FIBRINOLYSIS AND INHIBIT PLATELET AGGREGATION

Reuteur HD, Allium sativum and Allium ursinum : Part 2 Pharmacology and Medicinal Aplication, Phytomedicine 2 (1) : 73-91

PHARMACOLOGY ANTIPLATELET AGGREGATION

A PLATELET INHIBITING EFFECT HAD BEEN STUDIED IN A DOUBLE BLIND, PLACEBO CONTROLLED STUDY ON 60 VOLUNTEERS WITH GARLIC POWDER OVER 4 WEEKS. THE RESULT LED TO A SIGNIFICANT REDUCTION IN PLATELET AGGREGRATION
KIESELWETTER H.LUNG.F., JUNG. E.M., et al., EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 1993, 45 : 336-338 LEGNANI C., FRASCARO M, GUAZZALOCA G, et al, ARZZNEIMITTEL FORSCHING, 1993, 43(2) : 119-122

PHARMACOLOGY ANTI THROMBOXANE

CONSUMPTION OF GARLIC DAILY FOR PERIOD OF 16 WEEKS REDUCED THROMBOXANE BY ABOUT 80 %

ALI M., THOMSON., PROSTAGLANDINS, LEUKOTRIENES AND ESSENTIAL FATTY ACIDS, 1995, 53 : 211-212

PHARMACOLOGY ANTIPLATELET AGGREGATION

MECHANISM OF ACTION
REDUCED THE FORMATION OF THROMBOXANE FROM EXOGENOUS ARACHIDONATE INHIBIT THE DEGRADATION OF PHOSPHOLIPID INDUCED BY Ca2+ IONOPHORE REDUCE THE GENERATION OF THROMBOXANE AND 12-LIPOXYGENASE PRODUCT FROM ARACHIDONATE PLATELETS INHIBIT THE INCORPORATION OF ARACHIDONATE INTO PLATELET PHOSPHOLIPIDS
Srivasta K.C. Antiplatelet Constituens of Garlic and their Mechanism of Action. Abstrac Int Garlic Symposium Pharmacy, Pharmacology and Clinical Application of Allium sativum, 1991.

PHARMACOLOGY ANTIPLATELET AGGREGATION

SEVERAL IN VITRO STUDIES REPORT THAT GARLIC, OR ITS EXTRACTS, REDUCE PLATELET AGGREGATION INDUCED BY ADP COLLAGEN OR ADRENALIN
Apitz-Castro R, et al. Effect of Garlic and of three pure components isolated from it on human platelet aggregation, arachidonate metabolism, realcascreation and platelet ultrastructure. Thrombosis Research 32: 155-169, 1983.
Apitz-Castro R, et al. Ajoen, the antiplatelet priciple of Garlic, synergetically potentiates the anti-aggregation of prostacyclin, foskolin, indometacin and dipyridamole on human platelets. Thrombosis Research 42: 303-311, 1986.

GARLIC PHARMACOKINETICS
After oral administration, the total in all Organs reached in 4 hours, and in 8 hours it was reduced to half of the peak value.
(CHANG H.M, PHARMACOLOGY AND APPLICATIONS OF CHINESE MATERIA MEDIKA, WORLD SCIENTIFIC, PHILADELPHIA, 1986 : 88.

GARLIC TOXICITY
LD 50 OF THE GARLIC OIL IN MICE BY I.V INJECTION WAS 134,9 mg/kg BW.
LD 50 OF NATURAL DIALLYLTHIOSULPHONATE BY I.V WAS 70 mg/kg BW AND BY ORAL WAS 600 mg/kg BW. NO PATHOLOGICAL CHANGE WAS OBSERVED IN LIVER, SPLEEN, ADRENAL GLANDS, AND LUNG.

(CHANG H.M., PHARMACOLOGY AND APPLICATION OF CHINESE MATERIA MEDIKA, WORLD SCIENTIFIC, PHILLADELPHIA, 1986 : 88)

Analysis
Qualitative and quantitative assay for sulfer constituents (alliin, allicin etc.) : by High-Performance Liquid Chromatography or gas chromatography-mass spectroscopy methods.

Apii graveolentis Herbs (Celery)

Clasification Kingdom Division Class Subclass Ordo Family Genus Species : Plantae : Magnoliophyta : Magnoliosidae : Rosidae : Apiales : Apiaceae : Apium :Apium graveolens L

DESCRIPTIONS

1. 2. 3. 4. 5. 6. 7. 8. 9.

Aromatic smell, spicy, and thicken taste. Green texture until brownish. Leaves has complex fin, thin, brittle Sub leaves amount 3 7 pieces, 2 7,5 cm long, 2-5 cm wide. Main stalk has 12,5 cm long, rounded, stretch out, Sub stalk 1-2,7 cm long. Short stalk with stretch out skeleton. Sturdy root with cylinder shape. If it cut a half has 10 mm diameter. It have much Sub root with style like yarn and has 15 cm long, 2 mm wide, brownish texture until gray.

STRUCTURE AND SUBSTANCE

Apiose- Glu

O OH
OH

OH

O
O

Apiin
O HOCH 2 OH O OH HO

O OH

Apigenin

PHARMACOLOGY
1. Preface analysis showed that hypotension effect caused by chemoreseptor stimulation at karotid and aorta. 2. On the perfusion experiment believe that apigenin has vasodilator perifer effect 3. Another experiment showed that hypotension effect is related to nerve integrity sympatic system. 4. 200 g fresh celery can causes diuretic effect

Analysis

Qualitative and quantitative assay for Celery constituents (Apiin, Apigenin etc.) content by means of high-performance liquid chromatography.

Syzygium polyanthum folium

(Indonesian Bay-Leaf)
Clasification
Division Subdivision Class Spermatophyta Angiospermae Magnoliatae

Subclass
Order Family Species

Rosidae
Myrtales Myrtaceae Syzygium polyanthum (Wight) Waplers

DESCRIPTIONS

1. Tree with spreading branches and simple leaves

2. Indonesian bay leaf can reach a height of 90 feet although 60 feet is more common. 3. The flowers are pink and somewhat fragrant while the fruits are round; red at first, later brown. 4. The seeds are small and brown. 5. The dried brown leaves of Indonesian Bay-leaf are aromatic and somewhat sour

STRUCTURE AND SUBSTANCE

OH OCH 3

CH 2CH=CH

Eugenol

PHARMACOLOGY Antihypertension effect was showed by decreasing of arterial blood tension in male rat that became Hypertension by difference of decreasing model with verapamil.

Analysis
1.

2.

High-performance liquid chromatographyIndonesian Bay-leaf has 28 essential oils, e.g Eugenol Gas chromatography methodsContain of sesquiterpenes-lactone.

Rauwolfiae serpentina Radix

DESCRIPTIONS
Rauwolfiae Radix consist of dry root of Rauwolfia serpentina ( L). odourless, feel bitterly, brown colour length 5-15 cm

STRUCTURE AND SUBSTANCE

contains at least 1% alkaloids:
- reserpine, rescinnamine and deserpidine (group of reserpine) - ajmaline, raupine, yohimbine and serpentine (ajmaline group) - ajmalicine (raubasine)

N OH 3C N H H H

O OC OCH 3

C OCH 3

Reserpin

PHARMACOLOGY

Reserpine possesses antisympathicus (reduces catecolamines reserve, epinefrin and norepinefrin and central sedative properties ajmaline group cause a quickly acting, but short continuing blood pressure lowering by blockade of a- adrenoreceptors. Ajmalicine (= raubasine) works central and peripheral vessel-extending and contributes to the blood pressure-lowering total effect.

Analysis
Qualitative and quantitative assay for Celery constituents (Reserpin, serpentine etc.) content by means of highperformance liquid chromatography.

Temulawak
Klasifikasi botani temu lawak adalah sebagai berikut:

Divisi Sub divisi Kelas Ordo Keluarga Genus Spesies

:Spermatophyta :Angiospermae :Monocotyledonae :Zingiberales :Zingiberaceae :Curcuma :Curcuma xanthorrhiza Roxb.

Kandungan Kimia Rimpang Temulawak

Fraksi pati Fraksi kurkuminoid Fraksi minyak atsiri

Kurkuminoid Temulawak
Fraksi kurkuminoid rimpang temulawak terdiri atas dua komponen yaitu kurkumin dan desmetoksikurkumin, berwarna kuning atau kuning jingga, berbentuk serbuk dengan rasa sedikit pahit, larut dalam aseton, alkohol, asam asetat glasial, dan alkali hidroksida.

Rumus kimia : kurkumin = C21H20O6 (BM = 368) desmetoksikurkumin = C20H18O5 (BM = 338)

Struktur kurkuminoid
Kurkumin : 1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,6- diene-3,5-dione
O O

OH OMe OMe

OH

Desmetoksikurkumin :
O O

OH OMe

OH

PHARMACOLOGY

CURCUMIN INHIBITED THROMBOXANE B2 PRODUCTION

SRVASTA., DIKSHAR M., SRIMED R. C., 1985, THROMB.RES, 40:413-417

PHARMACOLOGY

CURCUMIN HAD DEMONSTRATED ANTI THROMBOTIC ACTION WHILE PRESERVING PROSTACYCLIN, AN INFLAMATORY MEDIATOR.

REFF : SRIVASTA, R., M. DIKSHIT, R.C.SRIMAL, B.N.,DHAWAN, 1985, AntiThrombotic effect of Curcumin, THROMBOSIS RES, 40 (3) : 413-417 SRIVASTA, R., V.PURI, R.C.SRIMAL, B.N. DHAWAN, 1986, Effect of Curcumin on Platelet Aggregation and Vascular Prostacyclin Synthesis, ARZNEIMFORSCH, 36 (4) : 715-17

PHARMACOLOGY
CURCUMIN HAD SHOWN NUMEROUS ANTI INFLAMATORY EFFECTS IN VITRO AND IN VIVO, SUCH AS ARACHIDONIC ACID PATHWAY ENZYME MODIFICATION, DIMINISHED NEUTROPHYL RESPONSES STABILIZATION OF INFLAMATORY CELL MEMBRANS, AND INHIBITION OF PLATELET AGGREGATION
REFF :

AMMON, H.P.T and WAHL, M., 1991., Pharmacology of Curcuma longa, PLANTA MEDICA, 57 : 5-6
SRIVASTA, K.C., 1989, Extract from two frequently consumed spices, Cumin (Cucinum cyminum) and tumeric (Curcuma longa), inhibit platelet aggregation and alter alcosaniod biosynthesis in human blood platelets, PROSTAGLANDIN LEUKOT ESSENT FATTY ACIDS, 37 (1) : 57-64.

PHARMACOLOGY

CURCUMIN INHIBITED PLATELET AGGREGATION MEDIATED BY THE PLATELET AGONIST EPINEPHRIN, ADP, PLATELET ACTIVATING FACTOR (PAF), COLLAGEN, AND ARACHIDONIC ACID

REFF : SHAH, B.H, et al., 1999., Inhibitory effect of Curcumin. A food spice from Tumeric on platelet activating factor and arachidonic acid mediated platelet aggregation through inhibition of Thromboxane formation and Ca++ signaling, BIOCHEM PHARMACOL., 58 (7) : 1167-1172.

PHARMACOLOGY
CURCUMIN INHIBITED PLATELET AGGREGATION INDUCED BY ARACHIDONATE, ADRENALIN, AND COLAGEN. IT INHIBITED THROMBOXANE B2 (TXB2) PRODUCTION FROM EXOGENOUS ARACHIDONATE WITH CONCOMITANT INCREASE IN THE FORMATION OF 12-LIPOXYGENASE PRODUCTS
REFF : SRIVASTA, K.C., BORDIA A., VERMA, S.K., 1995., Curcumin, a major component of food spice turmeric (Curcuma longa) inhibits aggregation and alters alcosanoid metabolism in human blood platelets, PROSTAGLANDIN LEUKOT ESSENT FATTY ACIDS, 52 (4) : 223-227

EFFECT OF TURMERIC EXTRACT ON THE CONVERSION OF ARACHIDONIC ACID TO TXB2 AND 12-HETE IN HUMAN PLATELETS
CONTROL DOSE 1 (10 g/mL) N=8 DOSE 2 (20 g/mL) N=8 DOSE 3 (40 g/mL) N=7 DOSE 4 (80 g/mL) N=3
(*) p < 0.05 REFF : SRIVASTA. K.C., 1989, PROSTAGLANDINS LEUKOT ESSENT FATTY ACID, 37 (1) : 57-64.

TXB2

12-HETE

2961 338
2122 646 (**) 1620 510 (**) 1168 548 (**) 898 414
(**) p < 0.01

10796 2301
11956 2620 (*) 13630 3021 (**) 15262 3801 (**) 17923 2575