WO2008062520A1 - Procédé d'expérimentation efficace de médicaments pour un agent antitrombotique - Google Patents

Procédé d'expérimentation efficace de médicaments pour un agent antitrombotique Download PDF

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WO2008062520A1
WO2008062520A1 PCT/JP2006/323302 JP2006323302W WO2008062520A1 WO 2008062520 A1 WO2008062520 A1 WO 2008062520A1 JP 2006323302 W JP2006323302 W JP 2006323302W WO 2008062520 A1 WO2008062520 A1 WO 2008062520A1
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blood
solution
volume
aqueous solution
anticoagulant
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Jun Kawasaki
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Jun Kawasaki
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/86—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood coagulating time or factors, or their receptors

Definitions

  • the present invention relates to an antithrombotic drug efficacy test method. More particularly, the present invention relates to an antithrombotic drug efficacy test method for quickly and easily determining the efficacy of an antithrombotic drug being administered for treatment.
  • Thromboembolism refers to a state in which blood has solidified in the heart or blood vessels. If blood is stopped by a thromboembolism, it will cause a lesion in the part nourished by the blood vessel, which can be fatal. Therefore, antithrombotic drugs are necessary to prevent thromboembolism.
  • antithrombotic drugs are necessary to prevent thromboembolism.
  • the present inventor has proposed a method for measuring the degree of blood clot formation on a thrombolast graph in the presence of an anticoagulant, when the platelet activity activator causes blood coagulation.
  • a patient who is receiving an antithrombotic drug is a system in which an anticoagulant such as henon or argatroban is added to a part of the collected blood (system X blood),
  • an anticoagulant such as henon or argatroban
  • a platelet activator such as adenosine diphosphate or collagen
  • thrombolasta taraf is measured at the same time, and R values of X system blood and Y system blood are compared. If the R value of the Y blood is significantly shorter than the R value of the X blood, it is determined that the efficacy of the antithrombotic therapy is not effective, and the R value of the Y blood is R of the X blood. If there is no significant difference from the value, the efficacy as antithrombotic therapy is judged to be effective.
  • Patent Document 1 Japanese Patent Application 2005—149183
  • the clotting time of the collected blood has the property that it varies depending on the person and the type and amount of the medicine taken by the same person.
  • the present invention is intended to provide an antithrombotic drug efficacy test method that is effective, reliably and rapidly implemented. That is, the present invention seeks to provide an antithrombotic drug efficacy test method for effectively, surely and quickly conducting various blood antithrombotic drug efficacy tests by shortening the time required for the preliminary test. It is. Furthermore, it is intended to provide an antithrombotic drug efficacy test method that can be easily, accurately, quickly and easily measured even by those who do not have specialized knowledge.
  • the gist of the present invention is indicated by itemized items as follows.
  • the amount of calcium chloride added to blood is the same for both X-system blood and Y-system blood, and the same amount of anticoagulant added to blood is the same for both X-system blood and Y-system blood.
  • Antithrombotic drug efficacy test method The amount of calcium chloride added to blood is the same for both X-system blood and Y-system blood, and the same amount of anticoagulant added to blood is the same for both X-system blood and Y-system blood. Antithrombotic drug efficacy test method.
  • antithrombotic drug efficacy test method wherein the anticoagulant solution is a heparin (undifferentiated heparin, low molecular heparin) aqueous solution or an argatroban aqueous solution.
  • the anticoagulant solution is a heparin (undifferentiated heparin, low molecular heparin) aqueous solution or an argatroban aqueous solution.
  • the final concentration containing the heparin aqueous solution is in the range of 0.1 Ol (UZmL) force and 0.1 (UZmL), and the final concentration containing the argatroban aqueous solution is from 0.1 (gZmL) to 5.0.
  • [5] The antithrombotic drug efficacy test method according to any one of [1] to [4], wherein the platelet activator solution is an adenosine diphosphate (ADP) aqueous solution or a collagen aqueous solution.
  • ADP adenosine diphosphate
  • the final concentration containing the adenosine diphosphate aqueous solution is 6. O / zM or more, and the final concentration containing the collagen aqueous solution is 1.0 gZmL or more. Antithrombotic drug efficacy test method.
  • the present invention relates to a system (X system blood) in which a salt calcium aqueous solution, an anticoagulant solution, and physiological saline are added to blood collected from a patient who has received antithrombotic drugs, and calcium chloride is added to the blood.
  • Antithrombotic drug efficacy test method for measuring the tropoelastograph and comparing the R values of X blood and Y blood in a system (Y blood) containing an aqueous solution, anticoagulant solution and platelet activator solution
  • Y blood containing an aqueous solution, anticoagulant solution and platelet activator solution
  • the antithrombotic drug efficacy test method As described above, it is possible to shorten the time required for the preliminary test and to effectively, quickly and accurately perform various blood antithrombotic drug efficacy tests. In particular, there is an effect that the time required for the antithrombotic drug efficacy test can be shortened. Furthermore, using the relationship between the ACT value obtained in advance and the final concentration of the anticoagulant solution to be added, even those who do not have specialized knowledge should conduct antithrombotic drug efficacy tests easily, accurately, quickly and simply. There is an effect that can be done.
  • clotting time is measured by other blood coagulometer.
  • Anticoagulation is performed in order to increase the clotting time of the blood (roughly synonymous with the R value on the thrombolast graph) to 30 to 40 minutes (thus suppressing thrombin partially or delaying production).
  • the amount of argatroban or heparin to be used as an agent is estimated and determined from the value of ACT from hemoclone (105 to 150 in normal adults) or the clotting time by other blood coagulometers. 2) Add reagent to start clotting of citrate blood sample on thrombolast graph.
  • the blood in the first channel (X system blood is a measurement channel), the blood is mixed with an aqueous solution of calcium chloride (sometimes abbreviated as chlorocalcium), an anticoagulant solution in an amount determined from the ACT value, Saline (hereinafter also referred to as raw food) is added, and in the second channel (channel for measuring Y-system blood), the blood is mixed with an aqueous solution of calcium chloride, an amount of anticoagulant solution determined from the ACT value, and platelets. Add a coagulant activator solution and measure the thrombolast graph at the same time.
  • R value a coagulant activator solution
  • the first channel is the measurement channel for X-system blood
  • the second channel is the channel for measuring Y-system blood
  • the second channel is the measurement channel for X-system blood
  • the first channel is for Y-system blood. It goes without saying that the channel can be measured.
  • 3) Comparing the R values of the first channel and the second channel if there is a significant difference, platelet stimulation in the second channel promoted clot formation in the second channel. It is determined that the platelet activity of blood is not greatly suppressed. If there is no significant difference, it is judged that platelet stimulation in the second channel cannot promote clot formation in the second channel, and the platelet activity of this blood is small and sufficiently suppressed.
  • the amount of argatroban aqueous solution or heparin aqueous solution used as the anticoagulant solution determined in 1) refer to the relationship between the ACT value obtained in advance and the optimum amount of argatroban aqueous solution or heparin aqueous solution to be added. And decide. Tables 11 and 12 show the ACT values and the empirically obtained optimal amounts (final concentrations) of argatroban or heparin to be added.
  • Reagents are also commonly referred to as The term “agent” is used as an anticoagulant, but when used as a reagent for antithrombotic drug efficacy test, the term “agent” is used.
  • the thrombolast graph is a device that observes the coagulation process of blood by the clot elasticity of whole blood.
  • Figure 1 shows a graph drawn with the clot elasticity on the vertical axis and the time change on the horizontal axis. Based on the measurement diagram shown in Fig. 1, the reaction time R value when the clot elasticity value width became 2 mm, the clot time K value and the clot elasticity value when the clot elasticity value width became 20 mm.
  • the maximum angle amplitude MA value and the angle ANG value when tangent is drawn in the graph of change in blood clot elasticity are obtained as numerical values.
  • the measurement operation itself is as simple as putting blood in a cuvette and starting the measurement.
  • the thrombolast graph used in the United States was a tronbolast graph C-TE G3000T manufactured by Moscope Co. and a Rotem GAMMA manufactured by Pentafuarm.
  • a test method using a thrombolast graph will be described.
  • the thrombolast graph to be used has at least a measuring section with 2 or more channels, and the measuring liquid volume is around 0.36 mL.
  • the amount of blood and reagents used in the antithrombotic drug efficacy test will be described.
  • the amount of reagent added to the blood is the specified volume ratio for both X-system blood and Y-system blood.
  • the salt and calcium added to blood has the same concentration and amount in both X and Y blood.
  • the anticoagulant solution is the same in both the X-type blood and the Y-type blood at the same concentration and the same amount.
  • the amount of X blood and Y blood used for the test is the same.
  • the calcium salt that can be stored in blood is 0.18 M calcium chloride aqueous solution (commercially available for intravenous injection) for 1 volume of anticoagulant solution and 1 volume of physiological saline for both system X blood and system Y blood.
  • the volume In the case of 20 mL containing 0.4 g of salty calcium; Otsuka Pharmaceutical, Fuso Pharmaceutical, Sanso, etc., the volume is 1 or more and 2 or less in this case (in this case, 0.18M calcium chloride aqueous solution
  • the volume can be any of 1.0, 1.5, 2.0, etc.), 0.2
  • the volume In the case of a 2M salt-calcium aqueous solution, the volume can be adjusted at a rate of 2, and in the case of a 0, 4M chloride chloride aqueous solution Capable of capacity 1
  • heparin undifferentiated heparin, low molecular weight heline
  • argatroban argatroban
  • Heparin or Argatroban final concentration force Heparin is 0. Ol (UZmL) force, etc. 0. l (UZmL) It is easy to mistake the number 1. Therefore, add the final concentration of argatroban from 0.1 (gZmL) to 5.0 (gZmL) so that the unit of volume is L). The actual amount to be added needs to be adjusted according to the length of the clotting time of the blood to be measured.
  • ADP adenosine diphosphate
  • collagen COL
  • adenosine diphosphate (ADP) or collagen is used as the platelet activator.
  • ADP can be adjusted so that its final concentration is 6 M or more.
  • Collagen (COL) should be prepared so that its final concentration is 1.0 g / mL or more. If the final concentration of ADP is at least 6 / zM or more, the thrombolast graph can be measured without problems. Similarly, if the final concentration of collagen is at least 1. O / z gZmL, the thrombolast graph can be measured without problems.
  • the maximum amount of ADP used is a final concentration of about M for collagen and about 10 gZmL for collagen.
  • the amount of reagent added to the cup of the thrombolast graph is such that the volume ratio of each reagent of aqueous chloride solution, aqueous solution of anticoagulant, and physiological saline is 1: 1: 1 in the system X blood. 30 / z L in the case of 1.5, 35 L in the case of 5: 1: 1, and 40 L in the case of 2: 1: 1.
  • the difference in the amount of addition is determined by the amount of calcium chloride in the reagent. For example, if the reagent mixing ratio is 1.3: 1: 1, the amount of reagent added is 33 / z. L.
  • actin can be calorieated as a blood coagulation promoter. If the amount of anticoagulant added increases, the measurement time of the thrombolast graph may become longer. In such a case, if actin is added, the thrombolast graph can be measured within an appropriate time.
  • the actin is preferably contained at a final concentration of 0.5 ng ZmL to 2.5 ng ZmL.
  • the amount of reagent such as a saline calcium aqueous solution, anticoagulant solution or physiological saline added to the blood is 10 L more than when no actin is added.
  • thrombolastograph There are two measuring instruments for the thrombolastograph, one from Haemoscope (Niles, IL, USA) and one from Rotem from Pentapharm (Munich, Germany). Blood volume is different. The total amount of Hemoscope thrombolast draft is specified as 0.36 mL, and when adding drugs, add 10 / z L per drug and determine the final concentration in it. Reduce the amount of blood to be added.
  • PENTAFU ARM Rotem has a constant blood volume of 0.30 mL, and as with calcium chloride, a 0.2 M aqueous solution of 20 mL of NaCl is recommended as in the case of the Thrombolastograph.
  • argatroban and collagen are each 10 L of calorie, and the total amount is 0.34 mL.
  • the maximum addition amount of this reagent is 40 L.
  • a maximum of 0.3 L is added. 4mL, minimum 0.33mL, no problem at all.
  • the maximum reagent volume of 40 L is added to 0.33 mL of blood, it becomes 0.37 mL, and the maximum volume of thrombolast graph is 0.36 mL.
  • the method is as follows: 0.1M of each of 18M salt ⁇ canorecum 5 L, 10 L, 20 L, and 30 L, 0.3 mL of whole blood and argatroban or heparin and collagen or ADP, which is a part of the reagent to be added this time.
  • the simulated dose was 10 L for each physiological saline, and a total of 20 L physiological saline was added to measure the degree of blood coagulation.
  • the time (minutes) at which the R point (the point indicating the start of solidification) appears on the thrombolast graph after the measurement was started was measured.
  • the R value is indicated by (mean person SD: mean person standard deviation). In the following examples, the R value is (mean It was shown by Shishi SD).
  • the optimum amount of 0.2M calcium chloride was examined in order to recalcified kennate blood.
  • the method is as follows: 0.2M calcium chloride 5 L, 10 L, 20 ⁇ L, 30 L, 0.3 mL whole blood and a dose simulating argatroban or henone and collagen or ADP as part of the reagent to be added this time
  • a total of 20 L of physiological saline was added to each physiological saline, and the degree of progress of blood coagulation was measured.
  • the time (minutes) at which point R (the point indicating the start of solidification) appears on the Trobolast graph after the measurement was started was measured.
  • the measurement results are shown in Table 2.
  • the R value is indicated by (mean SD: mean value standard deviation).
  • Table 2 shows that 0.2M calcium chloride 20 L is the optimum amount.
  • 0.2M salt calcium 5 L, 10 L is too little
  • 0.2 M calcium chloride 30 ⁇ L is too much
  • V deviation is also the point where
  • This example demonstrates the use of 0.4M calcium chloride to recalcified kennate blood. It is the Example which investigated the appropriate quantity.
  • the method is 0.4M calcium chloride 5 L, 10 / z LL, 15 ⁇ L, 20 / z L, 0.3 mL of whole blood and 1 part of the reagent added this time.
  • the amount of each physiological saline was 10 ⁇ L, and a total of 20 ⁇ L of physiological saline was added to simulate a collagen aqueous solution or an ADP aqueous solution, and the degree of progress of blood coagulation was measured.
  • the time (minutes) at which the R point (point indicating the start of solidification) appears on the thrombolast graph after the measurement was started was measured.
  • the measurement results are shown in Table 3. 0. 4M salt calcium 10 L has been shown to be optimal.
  • the 4M calcium chloride 5L was too little, and the 0.4M calcium chloride 15 ⁇ 20 ⁇ L was too much.
  • the amount of the calcium chloride aqueous solution added will be described based on an example in the case of following the blood addition method of Hemoscope Trombo Elastograph.
  • 20 ⁇ L of saline (saline) as the substitute dose of the reagent and the concentration and amount of salted calcium indicated in the table were added, and the total amount of blood was 0.36 mL. did.
  • Table 4 shows the results of 0.18M calcium chloride for recalcified kennate blood according to the blood scoring method of Hemoscope Thrombolastograph (method of adding whole blood to a total dose of 360 ⁇ ).
  • the result of the Example which investigated the optimal amount is shown.
  • the method is as follows: 0.1M salt ⁇ canoresum 5 L, 10 L, 20 L, L, each dose of a dose similar to argatroban or heparin and collagen or ADP as a part of the reagent Saline) 10 ⁇ L, total of 20 ⁇ L of raw food was added, and the blood volume was adjusted to 360 ⁇ L in total, and the degree of progress of blood coagulation was measured.
  • Example 1 was obtained by measuring the R value in accordance with the Rotem blood addition method of Pentafarm, and Example 2 was in accordance with the blood addition method of the Hemoscope thrombolast graph. R value was measured.
  • the addition amount of 0.18M calcium chloride aqueous solution is the optimum amount of 10 L and 20 L force
  • the addition amount of 0.2M calcium chloride aqueous solution is the optimum amount of 20 L. It has been shown that the optimum amount of 4M calcium chloride aqueous solution is 10 ⁇ L.
  • the amount of calcium chloride aqueous solution added to X-system blood and sputum system blood is 0.18M salt when mixing 1 volume of anticoagulant solution, 1 volume of physiological saline and calcium chloride aqueous solution. It can be seen that it is optimal to add 1 to 2 vol. Volume for aqueous calcium carbonate solution, 2 vol. For 0.2 wt. Calcium chloride aqueous solution, and 1 vol.
  • ADP adenosine diphosphate
  • collagen are used as platelet activator solutions in 4 ⁇ and 4 ⁇ g ZmL, respectively.
  • concentration 10 L (0. OlmL) and ADP (final concentrations of 4 ⁇ , 6 / ⁇ , 8 ⁇ ⁇ ⁇ ) with the final concentration of argatroban determined before this measurement in the presence of 0.2 M salt calcium 20 / zL ) And collagen (Col; final concentration of 0.5 ⁇ g / m 1. O The final concentration of mL 2.0 8 !
  • the concentration of the platelet activator solution added to the X-system blood and the Y-system blood is ADP (adenosine diphosphate) 6.
  • O / zgZmL It turns out that the above is the optimal amount.
  • Example 3 the optimum amount of actin (Actin from bovine muscle, A-3653, Sigma-Aldrich, St. Louis MO USA) as a blood coagulation promoter was examined.
  • actin Actin from bovine muscle, A-3653, Sigma-Aldrich, St. Louis MO USA
  • a rough optimum concentration of actin that promotes blood coagulation was determined by changing the final concentration from IngZmL to lpgZmL.
  • the R value was determined by a thromboelastograph. The results are shown in Table 9.
  • the final concentration of actin is 0.5 ngZmL (bottom stage) to 2.5 ng / mL (third stage), and the R value is significantly shorter than Control (without adding actin at all).
  • the final concentration of actin used to promote blood coagulation is 0.5 ngZmL (500 pgZmL) and 2.5 ng / mL.
  • Case 1 is a 71-year-old male with arteriosclerotic obstruction and renal failure who is taking 1 tablet (lOOmgZ day).
  • 1 volume of coagulant solution and 1 volume of platelet activator solution are stored.
  • Heparin at a final concentration of 0.lU/mL, argatroban is I got 3 M Caro.
  • the total liquid volume is 0.36 mL.
  • platelet aggregation caused by ADP shortens the R value by approximately 28%, and it can be determined that the current anti-platelet treatment of pretal lOOmgZ is insufficient.
  • a dose increase to 150mgZ is currently under consideration.
  • Case 2 is a 69-year-old male with arteriosclerotic obstruction and taking 2 pretal tablets (200 mg / day).
  • Anticoagulant solution is added at a rate of 1 volume and platelet activator solution 1 volume.
  • Heparin had a final concentration of 0.1 lUZmL
  • argatroban had a final concentration of 0.3 / z gZmL
  • ADP had a final concentration of 8.3 M calories.
  • the total volume is 0.36 mL. In this case, the reduction is 10 15%, and it can be determined that there is no significant difference and effective treatment is being performed.
  • Case 3 is a 63-year-old male with arteriosclerotic obstruction and taking 2 pretal tablets (200 mg / day).
  • 2 volumes of 0.2M salt-calcium aqueous solution Add 1 volume of anticoagulant solution and 1 volume of physiological saline, and add 2 volumes of 0.2M calcium chloride aqueous solution, 1 volume of anticoagulant solution and 1 volume of platelet activator solution to Y blood. It is added together.
  • Heparin at a final concentration of 0.1 lUZmL, argatroban at a final concentration of 1.2 g / mL, and ADP at a final concentration of 8.3 M calories.
  • the total liquid volume was 0.36 mL. In this case, the reduction is less than 10%, and it is judged that there is no significant difference, and effective treatment is considered.
  • Case 4 is a 54-year-old male with cerebral infarction taking 2 panalgin tablets (200 mgZ day).
  • 1 volume of coagulant solution and 1 volume of platelet activator solution are added.
  • the total volume is 0.36 mL. In this case, the reduction is 20% or less, and it is judged that there is no significant difference, and effective treatment is considered.
  • Case 5 is a 62-year-old male with atherosclerotic obstruction who is taking pretal 200 mg Z day.
  • 1 volume of anticoagulant solution and 1 volume of platelet activator solution are added.
  • Heparin at a final concentration of 0.1 lUZmL
  • argatroban at a final concentration of 1.2 ⁇ g / mL
  • ADP at a final concentration of 8.3 M calories.
  • the total volume is 0.36 mL.
  • there is a shortening of 20% or less and there is a delay in coagulation due to platelet aggregation stimulation, which is evidence that platelet activity is often suppressed, and it can be judged that treatment is sufficient.
  • Panaldine 2 tablets (200mg / day)
  • Case 6 is a 66-year-old male with atherosclerotic obstruction who is taking pretal 200 mg Z day.
  • 1 volume of anticoagulant solution and 1 volume of platelet activator solution are added.
  • Heparin was 0.2 UZmL and 0.1 LUZmL at the final concentration
  • argatroban was 0.3 / z gZmL and 0.2 / z gZmL at the final concentration
  • ADP was 8.3 M calorie at the final concentration.
  • the total volume is 0.36 mL.
  • the clotting time on the platelet aggregation stimulation side is long. The results show that the therapeutic effect is sufficient.
  • Case 7 is a 65-year-old male with cerebral infarction.
  • Add 1 volume of 0.18M calcium chloride aqueous solution, 1 volume of anticoagulant solution and 1 volume of physiological saline to system X blood, and 1 volume of 0.18M aqueous calcium chloride solution to system Y blood, anticoagulant 1 volume of drug solution and 1 volume of platelet activator solution are stored.
  • Argatroban has a final concentration of 4.0.
  • the total volume is 0.36 mL. In this case, the reduction is 20% or less, and it can be judged that there is no significant difference, and the treatment is sufficient.
  • Case 8 is a 58-year-old male with cerebral infarction who is taking Biaspilin lOOmgZ day.
  • Add 0.1 volume of 18M calcium chloride aqueous solution, 1 volume of anticoagulant solution and 1 volume of physiological saline to X blood, and 1 volume of 0.18M saline calcium solution to Y blood, anticoagulant Add 1 volume of solution and 1 volume of platelet activator solution! /
  • ACT value of 190 seconds heparin had a final concentration of 0.02 U / mL, argatroban had a final concentration of 0.75 gZmL, and collagen had a final concentration of 10 / gZmL.
  • Total liquid volume is 0. 36 mL.
  • Clinical trial example 9 is a 69-year-old male with arteriosclerotic obstruction and taking 2 pretal tablets (200 mg Z day). Add 2 volumes of 0.2M saline-calcium aqueous solution to system X blood, 1 volume of anticoagulant solution and 1 volume of physiological saline, and add 2 volumes of 0.2M calcium chloride aqueous solution to system Y blood. 1 volume of anticoagulant solution and 1 volume of platelet activator solution It is added together.
  • heparin was added at final concentrations of 0.03 U / mL and 0.02 UZmL
  • argatroban was added at final concentrations of 0.3 and 0.5 ⁇ g ZmL
  • collagen was added at a final concentration of 10 gZmL.
  • the total volume is 0.36 mL.
  • shortening of 20% or more was observed, and the antiplatelet action of pretal is considered insufficient.
  • Clinical trial example 10 was a 58-year-old male with a cerebral infarction. This is an example. Add 2 volumes of 0.2M salt-calcium aqueous solution, 1 volume of anticoagulant solution and 1 volume of physiological saline to X-system blood, and 2 volumes of 0.2M calcium chloride solution to Y-system blood. Add 1 volume of anticoagulant solution and 1 volume of platelet activator solution! Heparin was at a final concentration of 0.1 lU / mL, argatroban was at a final concentration of 1.2 g / mL, and collagen was at a final concentration of 8.3 / zg / mL. The total volume is 0.36 mL. In this case, the amount of argatroban is too small to be determined by argatroban, and heparin 20
  • Panaldine treatment is considered inadequate due to a reduction of more than%. After this, the R value of the thrombolast graph 7 months later was shown after changing to nospirin lOOmg / day. In any case, the treatment effect of bias pilin is considered to be insufficient with a shortening of 20% or more.
  • Case 11 was a 75-year-old male with atherosclerotic obstruction who was taking Pretal 200 mgZ and Epadele 900 mgZ.
  • 1 volume of 0.4M calcium chloride aqueous solution, 1 volume of anticoagulant solution and 1 volume of physiological saline are added to system X blood, and 1 volume of 0.4M saline calcium calcium solution is added to system Y blood.
  • 1 volume of anticoagulant solution and 1 volume of platelet activator solution are stored.
  • heparin has a final concentration of 0.07 UZmL
  • argatropane has a final concentration of 3.0 gZmL
  • collagen has a final concentration.
  • 10 / z gZmL The total volume is 0.36 mL.
  • Clinical trial example 12 is a 77-year-old male with atherosclerotic obstruction, taking pretal 200 mg Z day and Dorner 60 mg Z day. Add 1 volume of 0.4M saline-calcium water solution, 1 volume of anticoagulant solution and 1 volume of physiological saline to system X blood, and 1 volume of 0.4M calcium chloride aqueous solution to system Y blood. 1 volume of anticoagulant solution and 1 volume of platelet activator solution. For an ACT value of 111 seconds, heparin was at a final concentration of 0.03 and 0.06 UZmL, argatroban was at a final concentration of 3.0 gZmL, and collagen was at a final concentration of 10 g / mL.
  • the total volume is 0.36 mL.
  • Treatment with pretanol 200 mg / l and donoren 60 mg Z days is inadequate.
  • the R value of the thrombolast graph after 2 months is shown.
  • the power of the Arg3.0 data alone is insufficient.
  • the other three data show that all three are sufficient for this treatment.
  • Case 13 is a 59-year-old female with arteriosclerotic obstruction and taking pretal 200 mg Z day.
  • 1 volume of 0.18M calcium chloride aqueous solution, 1 volume of anticoagulant solution and 1 volume of physiological saline are added to X-system blood, and 1 volume of 0.18M aqueous solution of sodium chloride is added to Y-system blood.
  • 1 volume of coagulant solution and 1 volume of platelet activator solution are added.
  • ACT value of 193 seconds heparin at a final concentration of 0.03 UZmL, argatro The final concentration of van was 1.5 g / mL, and the final concentration of collagen was 10 g / mL.
  • the total volume is 0.36 mL. All show a reduction of 20% or more, and pretal 200mgZday is not adequately treated.
  • Case 14 was a 66-year-old male with atherosclerotic obstruction who was taking pretal 200 mgZ and ⁇ farin 2 mgZ.
  • 2 volumes of 0.2M calcium chloride aqueous solution, 1 volume of anticoagulant solution and 1 volume of physiological saline are added to system X blood, and 2 volumes of 0.2M aqueous calcium chloride solution are anticoagulated to system Y blood.
  • 1 volume of drug solution and 1 volume of platelet active solution are stored.
  • heparin was added at a final concentration of 0.03 UZmL, argatroban at a final concentration of 0.25 ⁇ g ZmL, and collagen at a final concentration of 1 mg / z gZmL.
  • the total volume is 0.36 mL.
  • Antiplatelet therapy is considered inadequate [Table 22]
  • Case 15 was a 62-year-old male with atherosclerotic obstruction who was taking pretal 200 mg / day. 2 volumes of 0.2M aqueous calcium chloride solution, 1 volume of anti-coagulant solution and 1 volume of physiological saline are added to the X-system blood, and 2 volumes of 0.2M calcium chloride solution are added to the Y-system blood. 1 volume of anticoagulant solution and 1 volume of platelet activator solution are added.
  • ACT value of 179 seconds heparin had a final concentration of 0.06 UZmL, argatroban had a final concentration of 1.5 ⁇ gZmL, and collagen had a final concentration of 10 ⁇ gZmL. The total volume is 0.36 mL. Heparin 0.06 is the only treatment that has been shown to be sufficient, but all three other argatroban measurements have been shown to be inadequate. Insufficient. [0063] [Table 23] Clinical trial 15
  • Clinical trial example 16 is a 62-year-old male with atherosclerotic obstruction and taking pretal 200 mg Z day. 2 volumes of 0.2M aqueous calcium chloride solution, 1 volume of anti-coagulant solution and 1 volume of physiological saline are added to the X-system blood, and 2 volumes of 0.2M calcium chloride solution are added to the Y-system blood. 1 volume of anticoagulant solution and 1 volume of platelet activator solution are added. For an ACT value of 190 seconds, heparin was added at a final concentration of 0.03 and 0.04 UZmL, argatroban was added at a final concentration of 0.75 and 1.
  • Case 17 was a 68-year-old male with atherosclerotic obstruction who was taking pretal 200 mg Z day.
  • ACT value of 190 seconds heparin was added at a final concentration of 0.1 lUZmL, argatroban was added at a final concentration of 0.4 // gZmL, and ADP was added at a final concentration of 8.3 / M.
  • the total liquid volume is 0.36 mL. All showed a reduction of 20% or more, and pretal 200 mg / day was judged to be inadequate.
  • Clinical trial example 18 is a 70-year-old male with atherosclerotic obstruction and taking pretal 200 mg Z day. 2 volumes of 0.2M saline-calcium aqueous solution, 1 volume of anti-coagulant solution and 1 volume of physiological saline are added to system X blood, and 0.2M calcium chloride aqueous solution is added to system Y blood. 2 volumes, 1 volume of anticoagulant solution and 1 volume of platelet activator solution are added. For ACT value of 199 seconds, heparin is added at a final concentration of 0.03 and 0.05 U / mL, argatroban is added at a final concentration of 1.0 and 2.
  • Case 19 is a case of a 65-year-old female cerebral infarction who is taking Panalgin 200 mg Z day.
  • the total liquid volume is 0.36 mL.
  • Heparin in (1) shows that only the thing stretched with 0.1 is sufficient for treatment, V, but the results for the other two heparins and argatroban are insufficient. Therefore, treatment with panalgin 200mgZ is considered inadequate.
  • Case 20 was a 68-year-old female antiplatelet drug (?), With normal platelet function. 1 volume of 0.18M saline-calcium aqueous solution, 1 volume of anticoagulant solution and 1 volume of physiological saline are added to X-system blood, and 1 volume of 0.18M calcium chloride aqueous solution is added to Y-system blood. Add 1 volume of anticoagulant solution and 1 volume of platelet activator solution. For ACT values of 178 seconds, argatroban was added at final concentrations of 1.0, 3.0 and 4.0 / X g / mL, and collagen was added at final concentrations of ⁇ / z gZmL. The total volume is 0.36 mL.
  • the amount of argatroban to be added is 2 to 3 times the amount of argatropan or heparin obtained from the case of kaolin (-) trial.
  • the platelet function that is not suppressed can be determined sufficiently by the kaolin-added card.
  • Case 21 was a 78-year-old female with antiplatelet drug (?) And normal platelet function.
  • 1 volume of 0.18M calcium chloride aqueous solution, 1 volume of anticoagulant solution and 1 volume of physiological saline are added to X blood, and 1 volume of 0.18M calcium chloride aqueous solution is added to Y blood.
  • argatroban was added at final concentrations of 0.25, 0.5, 1.0 and 1.5 g / mL, and collagen was added at a final concentration of 10 gZmL. The total volume is 0.36 mL.
  • the R value can be reduced to 30 to 40 minutes if 2 to 3 times the amount of argatroban to be added obtained from ACT in the Kaolin (1) trial is given to the Kaolin (+) trial. Also this power Pop and pin is used for the second time, and measurement is uneven.
  • Clinical trial 22 was a 78-year-old female antiplatelet drug (?), With normal platelet function. 1 volume of 0.18M calcium chloride aqueous solution, 1 volume of anticoagulant solution and 1 volume of physiological saline are added to X blood, and 1 volume of 0.18M calcium chloride aqueous solution is added to Y blood. Add 1 volume of coagulant solution and 1 volume of platelet activator solution! For ACT values of 176 seconds, argatropan was adjusted to 1.0, 2.0 and 2.5 g / mL at final concentrations, and collagen was adjusted to 10 gZmL at final concentrations. The total volume is 0.36 mL. Again, in the case of kaolin trials, the R-value can be almost certainly set to 30 to 40 minutes with an amount 2 to 3 times the amount of argatroban determined by ACT. It is also possible to determine uncontrolled platelets.
  • Clinical trial example 23 was a 77-year-old male with atherosclerotic obstruction who was taking Pretal 200 mg Z day and Dorner 60 mg Z day. Add 1 volume of 0.18M salt-calcium aqueous solution, 1 volume of anticoagulant solution and 1 volume of physiological saline to X blood, and 1 volume of 0.18M calcium chloride aqueous solution to Y blood. 1 volume of coagulant solution and 1 volume of platelet activator solution are stored. Argatroban has a final concentration of 0.5, 1.5 and 2.0 for an ACT value of 203 seconds
  • the total volume is 0.36 mL.
  • the measurement is sometimes unstable.
  • the antiplatelet treatment in this trial is inadequate.
  • Clinical trial example 24 is a 69-year-old male with arteriosclerotic obstruction and taking 2 pretal tablets (200 mg Zday). Add 0.1 volume of 18M calcium chloride aqueous solution, 1 volume of anticoagulant solution and 1 volume of physiological saline to X blood, and 1 volume of 0.18M calcium chloride aqueous solution, anticoagulant to Y blood. 1 volume of liquid and 1 volume of platelet activator liquid are added. For ACT values of 176 seconds, argatroban was given a final concentration of 1.5 and 4. O / z gZmL and collagen was given a final concentration of 10 gZmL. The total volume is 0.36 mL. Both kaolin (?) And kaolin (+) indicate that the platelet function is suppressed and that the difference is. Antiplatelet therapy is inadequate.
  • Case 25 was a 44-year-old male antiplatelet drug (?) In which the coagulation function was normal. Add 1 volume of 0.18M saline-calcium aqueous solution to system X blood, 1 volume of anticoagulant solution and 1 volume of physiological saline, and 1 volume of 0.18M salt calcium aqueous solution to system Y blood. One volume of anticoagulant solution and one volume of platelet activator solution are added. In addition to actin, argatroban was added at a final concentration of 1.0 and 2.5 g / mL and collagen was added at a final concentration of 10 gZmL for an ACT value of 185 seconds. The total volume is 0.36 mL. Platelet function is thought to have declined.
  • Case 26 is a case of a 46-year-old male antiplatelet drug (?) With normal clotting ability (aPTT, PT are normal).
  • aPTT normal clotting ability
  • 1 volume of drug solution and 1 volume of platelet activator solution are added.
  • argatroban was added at a final concentration of 1.5 and 2.5 ⁇ mL and collagen at a final concentration of ⁇ / z gZmL against an ACT value of 167 seconds.
  • the total volume is 0.36 mL. Even though the coagulation ability is normal, the platelet function is considered to have decreased.
  • Clinical trial 27 is a 48-year-old male antiplatelet drug (?) In which blood coagulation ability is normal. 1 volume of 0.4M calcium chloride aqueous solution, 1 volume of anticoagulant solution and 1 volume of physiological saline are added to the X system blood, and 1 volume of 0.4M salt calcium aqueous solution is added to the Y system blood. 1 volume of anticoagulant solution and 1 volume of platelet activator solution are added. In addition to actin, argatroban was added at a final concentration of 2.0 and 3.5 gZmL and collagen was added at a final concentration of 10 gZmL for an ACT value of 158 seconds. The total volume is 0.36 mL. In this case, platelet function is considered normal. The measurement of lactin (+) is unstable.
  • Clinical trial example 28 is a 67-year-old male with atherosclerotic obstruction and taking pretal 200 mg Z ⁇ .
  • 1 volume of 0.18M calcium chloride aqueous solution, 1 volume of anticoagulant solution and 1 volume of physiological saline are added to X-system blood, and 1 volume of 0.18M aqueous solution of sodium chloride is added to Y-system blood.
  • 1 volume of coagulant solution and 1 volume of platelet activator solution are added.
  • argatroban was added at 1.0 and 2.
  • C ⁇ gZmL and collagen at 10 gZmL at a final concentration for an ACT value of 181 seconds. The total volume is 0.36 mL.
  • the addition of actin shows a value closer to the measured value without the use of the coagulation promoter (the first measured value). It is considered that the measurement ability with the addition of actin is superior to the value with kaolin.
  • the power that pretal treatment is inadequate
  • the power that can be found with the addition of actin Kaolin treatment has shown that the treatment effect of pretal is sufficient.
  • the present invention is a test method for conducting an antithrombotic drug efficacy test appropriately, quickly and simply. Through the antithrombotic drug efficacy test method of the present invention, it greatly contributes to the medical, medical and pharmaceutical industries.
  • FIG. 1 is a diagram for explaining thrombolast graph measurement.

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Abstract

L'invention concerne un procédé d'expérimentation pour conduire une expérimentation d'efficacité de médicament pour un agent antitrombotique de façon rapide et simple. L'invention concerne un procédé d'expérimentation d'efficacité de médicament pour un agent antitrombotique dans lequel un trombo-élastographe est mesuré dans un système dans lequel une solution aqueuse de chlorure de calcium, une solution anticoagulante et une solution saline physiologique sont ajoutées à du sang prélevé d'un patient qui s'est vu administré l'agent antitrombotique (sang de système X) et un système dans lequel une solution aqueuse de chlorure de calcium, une solution anticoagulante et une solution activatrice des plaquettes sont ajoutées au sang (sang de système Y) et des valeurs R du sang du système X et du sang du système Y sont comparées. L'invention est caractérisée par le fait que la même quantité de chlorure de calcium et le même type et la même quantité de l'anticoagulant sont ajoutés respectivement au sang du système X et au sang du système Y.
PCT/JP2006/323302 2006-11-22 2006-11-22 Procédé d'expérimentation efficace de médicaments pour un agent antitrombotique WO2008062520A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000040963A1 (fr) * 1999-01-04 2000-07-13 Medtronic, Inc. Procede de determination de la reponse d'un inhibiteur de thrombocytes
JP2004503781A (ja) * 2000-06-09 2004-02-05 ヘモスコープ　コーポレイション 抗血小板剤をモニターする方法及び装置
WO2006126290A1 (fr) * 2005-05-23 2006-11-30 Jun Kawasaki Procede permettant de tester l’efficacite d’un agent antithrombotique

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000040963A1 (fr) * 1999-01-04 2000-07-13 Medtronic, Inc. Procede de determination de la reponse d'un inhibiteur de thrombocytes
JP2004503781A (ja) * 2000-06-09 2004-02-05 ヘモスコープ　コーポレイション 抗血小板剤をモニターする方法及び装置
WO2006126290A1 (fr) * 2005-05-23 2006-11-30 Jun Kawasaki Procede permettant de tester l’efficacite d’un agent antithrombotique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KAWASAKI J. ET AL.: "Effects of Platelet Agonists on Thrombolastogram in the Presence of Heparin or Argatroban", AMERICAN SOCIETY OF ANESTHESIOLOGISTS ANNUAL MEETING ABSTRACTS, 2003, pages ABSTR. NO. A-162, XP002995736 *
OKADA ET AL.: "Aspirin to Heparin no Sonzaika de Kesshoban wa Clot Keisei o Sokushin Shinai (Platelets would not accelerate whole blood clot formation in the presence of aspirin and heparin on thrombelastogram)", JOURNAL OF ANESTHESIA, vol. 19, no. SUPPL. P1-38.05, 2005, XP003022665 *

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