ORAL FIBRINOLYTIC:

A CHALLANGING
OPPORTUNITY
Moh Hasan Machfoed
Department of Neurology
School of Medicine Airlangga University
Dr. Soetomo Hospital Surabaya
Mobil Phone: 0812-353-8163
E-mail: m-hasan-m@telkom.net
1

Atherothrombosis
Perspective
2

Atherothrombosis is the leading cause of death worldwide

Those at risk of atherothrombosis

Local factors
Elevated prothrombotic factors: fibrinogen, CRP, PAI-1
Blood flow patterns, vessel diameter, arterial wall structure

Atherothrombosis
manifestations
(myocardial
infarction,
stroke, vascular
death)

Generalised
disorders
Obesity
Diabetes

Genetic
traits
Gender
Age

Lifestyle
Smoking
Diet
Lack of
exercise

Systemic
conditions
History of
vascular events
Hypertension
Hyperlipidemia
Hypercoagulable
states
Homocystinemia

Yusuf S et al. Circulation 2001; 104: 274653. 2. Drouet L. Cerebrovasc Dis 2002;13(suppl 1): 16.

Progression of atherosclerosis

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Arterial & venous thrombosis

1) Endothelial damage >>
platelet adhesion
2) Plaque rupture >>
platelet activation
3) Procoagulant
environment
4) Platelet agregation
5) Coagulation

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Plaque rupture & clotting mechanism

PRIMARY

AGGREGATION

Platelet Aggregation
Clotting

Fibrinogen

Fibrin
Hemostatic clot

SECONDARY

COAGULATION

0 min

Thrombin

5 min

10 min

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Reducing the risk of thrombosis

ANTITHROMBOTIC DRUGS

inhib

Coumarin
Abciximab
Tirofiban

http://dualibra.com/wp-content/uploads/2012/04/037800~1/Part%206.%20
Oncology%20and%20Hematology/Section%203.%20Disorders%20of%20Hemostasis/112.htm

Vascular Thrombogenesis Process

AUTOLYTIC

LUMBROKINASE
OPPORTUNITY

11

Common sense of Daily Practices

1. Vascular Thrombosis Obstruction cant be open
automatically Insufficiency of Autolytic

activity
2. Neither Anticoagulant oral nor anti pletelet
increase Autolytic activity Different

mechanism
3. Fibrinolytic oral is needed to increase Autolytic
activity common sense
Lumbrokinase (Fibrinolytic oral) has opportunity
for these cases

DLBS 1033: MECHANISME OF ACTION

Fibrinolytic

Stimulating the vascular endothelial cells to secrete

endogenous t-PA

Anticoagulation
Antiplatelet

Specific binding to fibrinogen Decrease

concentration of fibrinogen

Decrease the levels of Gmp-140, TXB2 and 5-HT

Inhibiting platelet activation and vasoconstriction

Positive Pleotrophic Effects

In addition, DLBS1033 also has Positive Pleiotropic Effects via down
regulate expression of genes related to vascular remodeling:
Anti inflammatory activities: (NF-KB, P-Selectin, TNF-, &
VCAM-1)
Plaque stabilization: MMP9
VSMC inhibition of proliferation & migration: JAK1/STAT1
Kurnia et al, 2011

FIBRINOLYTIC ACTION

Trisina et al, 2011

DLBS 1033 FIBRINOLYTIC ACTIVITY

(FIBRIN DISC METHOD)

Fibrinoliytic
activity

0h

1h

3h

6h

> 24 h

Trisina et al, 2011

DLBS 1033: CLOT LYSIS ACTIVITY

Clot lysis activity defined as percentage of destroyed blood clot weight after
incubated with samples compared to the initial frozen weight.
DLBS1033 yielded in the increased thrombolytic activity compared to
control
Suhartono et al, 2008

DLBS 1033: ANTI PLATELET AGGREGATION ACTIVITIES

In vitro study using human blood with platelet aggregation activators

(ADP and thrombin). DLBS1033 totally inhibits platelet aggregation at
concentration above 60 mg/ml
Trisina et al, 2011

Changes in coagulation and t-PA after the treatment

of cerebral infarction with lumbrokinase
Case: Acute cerebral infarction (acute ischemic
stroke) Onset before treatment around 3 + 1 days

Sample size: n = 51, 47-88 years old

Test group (n = 31) Lumbrokinase po, tid + dextran
Control group (n = 20) Dextran

Treatment duration : 28 days

Clinical Hemorheology and Microcirculation 2000; 23: 213 8

Changes in the Plasma Fibrinogen Level after the

treatment of cerebral infarction with lumbrokinase
Plasma Fibrinogen Level between Treatment and Control Groups

* p < 0.05 vs week-0

Clinical Hemorheology and Microcirculation 2000; 23: 213 8

Changes in coagulation and t-PA after the treatment

of cerebral infarction with lumbrokinase
Plasma t-PA Activity between Treatment and Control Groups

* p < 0.05 vs week-4, **p < 0.01 vs week-1&2

Clinical Hemorheology and Microcirculation 2000; 23: 213 8

Lumbrokinase significantly potentiated the activity of adenylate cyclase, increased the

cAMP level in vivo, remarkably inhibited the rise of rat platelet intracellular Ca2+

Verma et al, 2011

PLEIOTROPHIC EFFECT
OF
DISOLF (DLBS 1033)

ANTI-INFLAMMATORY ACTION OF DLBS 1033

Decrease P-selectin level
Decrease VCAM-1 level
Decrease TNF level
Decrease NFKB level
Inhibition of VSMC proliferation & migration
Decrease STAT-1 level
Decrease MMP-9 level

Kurnia and Tjandrawinata. Medicinus 24(1):18-24, 2011

Adhesion Molecules: Anti-inflamation

P-selectin leukocytes recruitment

atherosclerotic plaque formation
Kurnia and Tjandrawinata. Medicinus 24(1):18-24, 2011

VCAM-1 adhesion of lymph, monocy, eosin, basoph

plaque formation
Kurnia and Tjandrawinata. Medicinus 24(1):18-24, 2011

CLINICAL USES OF DISOLF

Based on the mechanism of action and
pleiotropic effect DISOLF can be given
to the cases as follows:
1. Ischemic Stroke
2. Atherosclerosis
3. Acute Limb Ischemia
4. Deep Vein Thrombosis (DVT)
5. Venous Thromboembolism (VTE)
6. Pulmonary Emboli
7. Heart diseases

Double Blind Randomized clinical trial on

Bleeding Profile and Clinical Outcome Ischemic stroke patients
Clinical outcome results on 90th day
Clinical Outcome
Barthel Index
Score:
- Aspirin
- Clopidogrel
- DLBS 1033
SSGM :
- Aspirin
- Clopidogrel
- DLBS 1033

Baseline

Day-90

Delta

83,75
75,20
79,21

98,10
91,85
97,79

14,35
16,65
18,58

<0,001
0,001
<0,001

31,30
28,75
29,21

36,15
33,90
35,95

4,85
5,15
6,74

< 0,001
0,002
<0,001

Aspirin, Clopidogrel and DLBS 1033 showed significant statistical difference to

improve clinical outcome on stroke patients, based on Barthel Index Score and
SSGM after 90 days of administration.
Setyopranoto et al, 2012

Ziyuan, 2009

Zhang et al, 2013

Wang et al, 2013

Policherla et al, 2015

DISOLF affected CIMT Reduction

Open study of DLBS1033 on the progression of CIMT in
atheroscrelotic subjects (n = 18): DLBS1033 significantly reduced
carotid intima-media thickness ( CIMT )

Gunawan H, 2012. The effect of DLBS1033 on the progression of CIMT in subjects with atherosclerosis. Jakarta

The Effect of Disolf (DLBS 1033) in

Peripheral Arterial Disease (PAD)
Randomized Clinical Controlled Trial, 20
number of subject, for 2 weeks evaluation
Measurement : ABI ( Ankle Brachial Index )
Dose: DISOLF 3 x 1 Versus Placebo
A low ABI indicate narrowing or blockage of the arteries in the
legs, increasing the risk of circulatory problems

Ndraha S et al. Depart of Intern Med UKRIDA

Christian University, Jakarta-indonesia 2013

34

Results after 2 weeks

CONCLUSION: DBLS 1033 showed to improve ABI in patients

with intermittent claudication.

Oral Lumbrokinase in
Stable Angina Pectoris

36

Improved Myocardial Perfusion in Stable

Angina Pectoris by Oral Lumbrokinase:
A Pilot Study
M. Kasim, A. A. Kiat, M. S. Rohman, Y. Hanifah, and H. Kiat,
Improved myocardial perfusion in stable angina pectoris by
oral lumbrokinase: a pilot study, Journal of Alternative and
Complementary Medicine, vol. 15, no. 5, pp. 539544, 2009.

10 stable angina pectoris patients were randomly

selected from proved Coronary artery disease
(CAD) population in National Cardiovascular
Center Harapan Kita.
Diagnosis of CAD confirmed by MSCT or coronary
angiography examination.

MRI PERFUSION IMAGING (MPI) Improved Perfusion

after 1 month in lumbrokinase in SAP (70%)

CONCLUSION: Lumbrokinase reduction in the degree and

extent of inducible myocardial ischemia without bleeding
complication

DLBS 1033:
PRODUCT PROFILE
Each tablet contains 490 mg DLBS1033 Lumbricus rubellus

indications: Helps blood circulation

Dose: Adults 1-2 tablets 3 times a day, - 1 hour before
meals.
Warning and attention: Only used on medical advice
During the use of this product, please consult the doctor on

a regular basis

CONCLUSION
With the action mechanisms as antipletelet agregation, antithrombosis,
fibrinogenolytic and thrombolytic,
Lumbrokinase (DLBS 1033) can be used
as a Challenging Fibrinolytic Drug

TERIMA KASIH

BANJARMASIN, MHM, 15-04-2016