The Effects of DLBS1033 on Haemostasis Parameters in Healthy Volunteers
Condition: Healthy
Study type: Interventional
Phase: Phase 2

Summary: 
      DLBS1033 is bioactive protein fraction which extracted from Lumbricus rubellus earthworm.
      This earthworm comes from Pengalengan, West Java, Indonesia. DLBS1033 possesses 8 major
      proteins with molecular weight below 100 kDa, so its named as Lumbricus Low Molecular weight
      Proteins (LLP). This enzym can be transported to the bloodstream via intestinal epitel.
      Structure of DLBS1033 looks like lumbrokinase. Lumbrokinase is enzym that consist of 6
      isoenzyme serine protease. As a drug that consists of serin protease enzym, suspected that
      the mechanism of action of DLBS1033 similar with lumbrokinase, especially as plasminogen
      activator in fibrinolytic system. In vitro study by Trisina et al showed that DLBS1033 has
      fibrinogenolytic activities on fibrinogen α, beta, and gamma chain, decreasing platelet
      aggregation and clotting time was prolonged. Until now, the mechanism of action and effects
      of DLBS1033 on human fibrinolytic and coagulation system still unknown. Therefore, the aim of
      this clinical trial is to evaluate the effects of DLBS1033 on human fibrinolytic and
      coagulation system on healthy subjects.
    

Detailed description: 
      Fibrinolysis is a process to lyse clot formed by thrombin. It starts with activating
      plasminogen to plasmin by the endogenous tissue plasminogen activator (tPA) and urokinase
      plasminogen activator (uPA). These activator are found in the endothelium, granulocytes and
      monocytes. Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of tPA and uPA)
      and α2-antiplasmin is major inhibitor of plasmin. Plasmin wil degrade soluble fibrinogen and
      fibrin to produce fibrinogen degradation products and fibrin degradation products,
      respectively.

      Lumbrokinase has been investigated in animal studies. Kim et al was conducting on rats by
      administered freeze-dried powder of Lumbricus rubellus earthworm orally. This study showed
      that earthworm powder is valuable for the prevention and/or treatment of thrombotic
      conditions. Similar conclusion also shown on study by Lee et al, which compared
      antithrombotic and fibrinolytic activities of lumbrokinase SPP-501 (extracted from Eisenia
      andrei earthworm) with urokinase and t-PA in a thrombosis model of rat vena. The results of
      this study were decreasing of thrombus weight, shortening of euglobulin lysis time (ELT), and
      reducing platelet aggregation of rat which given SPP-501.

      Conclusion from several clinical trial similar with several studies on animal. From study
      which was conducted by Jin et al on 51 cerebral infarct subjects which were given 3 times 400
      mg lumbrokinase (n = 31) or control (n = 20) for 28 days. In the treatment group, kaolin
      partial thromboplastin time (KPTT) was prolonged, t-PA activity and D-dimer level increase,
      and fibrinogen decreased significantly. It is concluded that mechanism of lumbrokinase as
      oral antithrombotic and fibrinolytic are by inhibition of coagulation intrinsic pathway and
      activate fibrinolytic pathway by increasing t-PA activity. Fibrinolytic activity was also
      concluded by Rey, who was conducted study on 28 diabetic foot ulcer subjects, which were
      given 3 times 500 mg lumbrokinase per day (n = 14) for 7 days, or placebo. On this study, in
      the treatment group mean of D-dimer was increased.

      From many clinical trials, it is concluded that effects of lumbrokinase have seen after
      several days. It is different with intravenous fibrinolytic enzym, such as streptokinase and
      t-PA, which effects have seen soon after it was used. Therefore oral lumbrokinase could not
      replace the function of intravenous fibrinolytic enzym,that was used on acute thrombosis.
      Based on antithrombotic and fibrinolytic activity, lumbrokinase might used as secondary
      prevention after acute thrombosis, such as myocard infarct and stroke. Some researchers have
      started clinical trials about that hypothesis.

      Pilot study by Kasim et al was used a lumbrokinase in 10 patient with stable angina pectoris.
      This study showed that 70% of total sample receiving lumbrokinase had a significant decrease
      in summed stress score of perfusion imaging and better perfusion in viable myocardium after
      30 days of lumbrokinase treatment.
    

Intervention name(s): DLBS1033; placebo
Intervention type(s): Drug; Drug
Intervention description(s): The study drug is enteric coated DLBS1033, which contain 490 mg bioactive protein fraction.; Placebo is made with same size and shape with study drug.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: lumbrokinase; fibrinolytic; plasmin-antiplasmin complex; euglobulin clot lysis time; platelet aggregation