Micro and Macrovascular Disorder the Role of Lumbrokinase

dr. Khomimah, [email protected]

RS Islam Pondok Kopi Jakarta Timur; RS Awal Bros Kalimalang; RS Antam Medica Jakarta Timur

Source: IDF Diabetes Atlas, 6th edn. Brussels, Belgium: International Diabetes Federation, 2013. http://www.idf.org/diabetesatlas

Pathophysiology of type 2 diabetes

Cernea S & Raz I. Diabetes Care 2011;34(suppl 2):S264–S271

CNS, central nervous system; GI, gastrointestinal; T2DM, type 2 diabetes mellitus

Adipocyte

CNS

Incretin deficiency

GI tract

Altered fat metabolism

INSULIN RESISTANCEINADEQUATE INSULIN

SECRETION↑ HEPATIC GLUCOSE

PRODUCTION

↑ BLOOD GLUCOSE

Hyperglucagonaemia↑ hepatic sensitivity

to glucagon

cellsα cells

SkeletalMuscle

Pancreas

Muscle

Kidney

Enhanced glucose reabsorption

Slide 7

The goal of diabetes management is to secure optimal glycemic control to avoid complications

Diabetic

retinopathy

Leading cause

of blindness

in working-age

adults1

Diabetic

nephropathy

Leading cause of

end-stage renal disease2

Cardiovascular

disease

Stroke

1.2- to 1.8-fold increase in stroke3

Diabetic

neuropathy

Leading cause of non-

traumatic lower extremity

amputations5

75% diabetic patients

die from CV events4

1Fong DS, et al. Diabetes Care 2003;e 26 (Suppl.1):S99–S102. 2Molitch ME, et al. Diabetes Care 2003; 26 (Suppl.1):S94–S98. 3Kannel WB, et al. Am Heart J 1990; 120:672–676. 4Gray RP & Yudkin JS. Textbook of Diabetes 1997. 5Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl.1):S78–S79.

Microvascular Macrovascular

Diabetic Foot

Erectile DysfunctionThe most secretive

Complication of DM

Can affect any part of the body, at any time

It is most common precursor to Coronary heart disease and heart attack

It also causes stroke by affecting the arteries in the neck

One of the most common form of vascular disease in PAD

Metabolic memory: A vascular perspective

Hyperglycemia and vascular outcome

Hyperglycemia activates multiple and complex pathogenetically relevant pathways.

• Inflammatory processes lead to a thickening ofthe basal membrane of microvessels andperivascular fibrosis resulting in micro vascularendpoints in the most susceptible organs, suchas renal insufficiency and retinopathy.

• The structural changes also result in functionalimpairment and a reduction in blood flowregulation, which in turn reduces macrovascularendothelial function.("Micro/Macro Interaction”).

• The loss of endothelial protection may lead tothe subsequent development of atherosclerosis.

• The structural changes within themicrocirculation may account for building up a

“metabolic memory”.

Jax Cardiovascular Diabetology 2010, 9:51

The Vascular Continuum. Conductance arteries mediate downstream effects to resistance arteries and capillaries. If

microcirculation is impaired by perivascular fibrosis as in diabetes, upstream effects influence conductance arteries.

Jax Cardiovascular Diabetology 2010, 9:51

Japanese Journal Of Physiology, 41, 1991A Novel Fibrinolytic Enzyme (Lumbrokinase)

Extracted From The EarthwormHisashi MIHARA, Et Al

Abtract• A Strong Fibrinolytic Enzyme Was Readily Obtained In Saline Extract Of The Earthworm• It Hydrolyzed Not Only Plasminogen-rich Fibrin Plate, But Also Plasminogen-free Fibrin

Plates

LumbrokinaseReseached And Developed ByThe Institute Of BiophysicsChinese Academy Of Sciences

Safe And Effective Supportive Measure In The Management Of Diabetes MellitusMicrovascular And Macrovascular Complications Prevention And Treatment

Activation of the coagulation cascade occurs through release of tissue factor (extrinsic pathway). This leads to the generation ofthrombin which activates fibrinogen by cleavage of fibrinopeptides A and B resulting in polymerisation to form the fibrin clot. FactorXIIIa catalyses the formation of covalent cross-links between fibrin molecules which enhances the stability of the clot. Fibrinolysis isinitiated by the activation of plasminogen to plasmin by tissue-plasminogen activator (t-PA) and urinary-type plasminogen activator (u-PA). The main inhibitors of fibrinolysis are plasminogen activator inhibitor-1 (PAI-1) and α2-antiplasmin.

Thromb Haemost 2011; 105 (Suppl 1): S43–S54

LUMBOKINASEMechanism of Action In The Management 0f Thrombotic Disorders

1. Directly dissolve fibrinogen and fibrin, convert plasminogen to plasmin, increase endogenous human t-PA activity (Fibrinolytic)

2. Inhibiting platelet activation and aggregation (Anti Platelet)3. Inhibiting of ICAM-1 expression (Anti Coagulation)Plus (+) Fibrinogenolytic

1. Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing, China, 2. Department of Natural Sciences, Northeastern State University, Broken Arrow, Oklahoma, USA, and 3. harmaceutical School, Peking University, Beijing, China

3 in 1

Microcirculation were improved significantly after treatment in both groups (P <0.05).

Compared with the control group, the microcirculation improvement in the treatment group was significantly better

(P <0.05).

Conclusions

The Diamicron Plus Lumbrokinase Capsules Can Effectively Treat Microcirculatory Impairment In Diabetes Mellitus Without

Any Major Adverse Reactions.

Parameter

Table 1. Nailfold microcirculation indicators before and after treatment

* vs. Pre-Tx, p<0.05; ∆ vs.control, p<0.05

Evaluation : 1) Effective: abnormal sensations, decreased muscle tone & strength improved / disappeared; improvement in knee & achilles deep tendon reflex. 2) Ineffective: no improvement in abnormal sensations, decreased muscle tone and strength; no improvement in knee and achilles deep tendon reflex.

(X2=21.56, P<0.01). It explains that lumbrokinase is effective in treating diabetic peripheral neuropathy

Observation of the Effectiveness of

Treating Diabetic Peripheral Neuropathy by Lumbrokinase

Treatment Method: • Apply vitamin B1 20 mg 3 tid, muscle injection of vitamin B12 500μg once a day on top of diet control and

blood sugar lowering drugs• Treatment group has lumbrokinase 460 mg tid 30 minutes before meal. For 4 weeks.

XiuLan Gu, GuanYin Lee, Lian Lian Chinese Journal Of Primary Medicine and Pharmacy 2003; 10(7): 665.

Medical Management of Acute Limb Ischemia (PVD)The Role of Lumbrokinase

Kasim, M. et al The Journal of Alternative and Complementary Medicine; 2009; 15 (5): 539543

Diagnosis• 60 yrs man• Stage IIB Acute Limb Ischemia (PVD)• Atrial fibrilation with normoventricular response• Moderate mitral stenosis• Type-2 DM• Stage-1 hypertension

Treatment• Surgical Procedures (Surgical Thrombectomy) Refused• Tromboles (Lumbrokinase), 3 x 3 kalsul• Cilostazol, 2 x 100mg• Digoxin, 1 x 0,25mg• ISDN, 3 x 10mg• Metformin, 2 x 500mg• Irbesartan, 1 x 100mg

Day-4Pain and numbness of both legs disappearPatient only felt stiffness on dorsum pedis and toesPhysical examination: weak pulsation of tibialis anterior and dorsalis pedis arteries

Day-15CT angiography: better contrast flow on bothn legsAfter 2 weeks of treatment with Lumbrokinase discharged with good conditions

Day-50 CT angiography: normal contrast flow on both legs

• Tromboles (lumbrokinase) could be considered as an alternative medicaltreatment for acute limb ischemia, especially in patient who refused surgicaltreatment.

• The role of Tromboles (lumbrokinase) as a treatment option of acute limb ischemianeed further evaluation on large, well design, study.

Conclusion

Methods10 stable angina pectoris patients were randomly selected from proved CAD population innational cardiovascular center Harapan Kita.

Diagnosis of CAD determined by typical chest pain symptom and confirmed by MSCT orcoronary angiography examination.

They were given additional 2 capsules of Tromboles (containing 250 mg lumbrokinase for eachcapsul) three times daily for 30 days to a standard therapy including nitrate, ß blocker, statinand aspirin.

Perfusion imaging 99mTc-Sestimibi was used to evaluate the perfusion and viability ofmyocardium before and after treatment using DSX rectangular gamma Sophy camera.

One month treatment of oral Tromboles (lumbrokinase) resulted in an improvement myocardialperfusion in stable angina pectoris with metabolic syndrome without bleeding complication

Improved Myocardial Perfusion in Stable Angina Pectoris by Oral Lumbrokinase (TROMBOLES)

A Pilot Study

Kasim, THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE 2009;15(5): 539-44

Figure 2.A case example of a patient's stress myocardial perfusion before and atthe end of 30 day treatment with Lumbrokinase (TROMBOLES).

Corresponding representativeapical (a), mid (b) and basal (c) short axis, and mid vertical long axis (d)tomographic perfusion images demonstrating significant reduction in theextent and degree of inducible ischemia in the anterior (arrows) andlateral (arrow heads) left ventricular wall.

Oral Lumbrokinase

TROMBOLESIMPROVES REGIONAL MYOCARDIAL PERFUSION

in Patients with Stable Angina

ObjectiveAssessment

Chin Med J 2013;126 (21)

• To assess the effect of one year therapy with oral lumbrokinase enteric-coated onsecondary ischemic stroke prevention.

• This is a multicenter, randomized, parallel group and controlled study that begantreatment in hospitalized patients with ischemic stroke and continued for 12 months.

• A total of 310 patients were enrolled:• 192 patients in the treatment group (standard stroke Tx plus enteric-coated

lumbrokinase capsul)• 118 patients in the control group (standard stroke Tx)

• Primary Outcome:All cause mortality; any event of reccurent IS/TIA, haemorrhagic stroke. MI/Angina,and other noncerebral ischemia or haemorrhage

Blood Indexes

(P < 0.05)

(P 0.013)

(p >0.05)

(p >0.05)

The Anti-thrombosis Action Prevention Of Pathologic Coagulation due toInhibiting 0f ICAM-1 Expression

European Journal Of Pharmacology 2008

12.12

12.3212.312.23

Before After

PT (seconds)Lumbrokinase Control

30.0430.3

30.45

30.73

BEFORE AFTER

APTT (seconds)Lumbrokinase Control

Unchanged, p >0.05

Unchanged, p >0.05

Lumbrokinase • Does Not Affect Physiological

Coagulation System• It May Reduce The Risk Of

HemorrhageChin Med J 2013;126 (21)

the content of PT and APTT were

unchanged (P >0.05)

1,38±0.52 1,40±0.79

1,62±0.561,59±0.69

1.2

1.3

1.4

1.5

1.6

1.7

LEFT RIGHTIM

T, m

m

Bilateral Carotid IMT

Control GroupBEFORE TX

AFTER TX

*P <0.001*P =0.055

CIMT – A Surrogate MarkerPerbaikan CIMT mengindikasikan

perbaikan atherosclerosis

diseluruh tubuh

1,26±0.49 1,25±0.51

1,09±0.40

1,06±0.35

0.9

1

1.1

1.2

1.3

LEFT RIGHT

IMT,

mm

Bilateral Carotid IMT

Treatment Group BEFORE TX

AFTER TX

*P <0.001

Intima-Media Thickness

(IMT)

Vascular endpoint (n(%))

Kaplan Meier survival

analysis showed a

significant reduction of

total vascular events,

falling by 4,7% in

treatment group

6,78 % 2,08 %

Vascular Endpoint

CONTROL; Standard Stroke TX

TREATMENT; Std Stroke TX + Tromboles

Summary• Diabetes is chronic progression disease, need to early intensification therapi to prevent

complications• Microvascular and macrovascular • The Role of Lumbrokinase in The Management of Thrombotic Disorder

Microvascular Disorders Diabetic Polyneuropathy

Improved Microcirculation and Nerve Conduction Diabetic Nephropathy

Markedly Reduced Albuminuria Improved the glomerulosclerosis and tubulointerstitial fibrosis

Micro/Macrovascular Disorders Stable Angina Pectoris: Improved Myaocardial Perfusion Acute Limb Ischemia (ALI): Improved Symptoms ang Signs at day-4Macrovascular Disorders as an Oral Fibrinogen Depleting Agent: Improved Carotid Atherosclerosis and

Improved Vascular Endpoints• Safe And Effective Supportive Measure In The Management Of Diabetes Mellitus Microvascular And

Macrovascular Complications Prevention And Treatment

After 6 mo Therapi:

NIHSS scores were signifivanly improve in both group (p<0.001)

After 1 year:

A further reduction in both group,significance reduction in treatment group (p,0.001)

Penderita angina pektoris diberikan tambahan Tromboles sehari 3 kali 2 kapsul,setelah penggunaan selama 30 hari, dievaluasi dengan Tc-Sestamibi didapatibahwa 70% dari penderita yang mengkonsumsi Tromboles perfusi myocardmembaik bermakna vs kelompok tanpa Tromboles, dan rasa nyeri dadamenghilang (p<0.001), tanpa efek samping.

One month treatment of oral Tromboles (lumbrokinase) resulted in an improvement myocardialperfusion in stable angina pectoris with metabolic syndrome without bleeding complication

MICRO AND MACROVASCULAR DISORDERS

The Role of TROMBOLES