CN101642570B - Application of carbon monoxide-releasing molecules and heparin in preparing medicament for treating sepsis - Google Patents
Application of carbon monoxide-releasing molecules and heparin in preparing medicament for treating sepsis Download PDFInfo
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- CN101642570B CN101642570B CN200810043693A CN200810043693A CN101642570B CN 101642570 B CN101642570 B CN 101642570B CN 200810043693 A CN200810043693 A CN 200810043693A CN 200810043693 A CN200810043693 A CN 200810043693A CN 101642570 B CN101642570 B CN 101642570B
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Abstract
The invention provides application of carbon monoxide-releasing molecules and heparin in preparing a medicament for treating sepsis. The carbon monoxide-releasing molecules are combined with the ultramicro heparin to improve the coagulation defects of the sepsis, the control of the concentration of the carbon monoxide-releasing molecules and the heparin is relatively easy and correct, the carbon monoxide-releasing molecules and the heparin can be conveniently added when used for a long time, simultaneously the consumption and side effect of the heparin are reduced, and the carbon monoxide-releasing molecules and the heparin can meet the requirement of clinical application. The carbon monoxide-releasing molecules are combined with the ultramicro heparin to improve the coagulation defects of the sepsis, the control of the concentration of the carbon monoxide-releasing molecules and the heparin is relatively easy and correct, the carbon monoxide-releasing molecules and the heparin can be conveniently added when used for a long time, and the carbon monoxide-releasing molecules and the heparin can meet the requirement of clinical application.
Description
Technical field
The present invention relates to the new purposes of carbon monoxide-releasing molecules and heparin, specifically, relate to a kind of carbon monoxide-releasing molecules associating ultra micro dosage heparin, the medicine of coagulation disorders during early stage application of treatment sepsis.
Background technology
Sepsis is severe trauma, shock and infects the back common complication; Further develop and to cause septic shock, multiple organ dysfunction syndrome (MODS); Even if the modern times with clinic study and the high development of Intensive Care Therapy means on the basis; Clinical treatment still produces little effect, and mortality rate is high.Research shows that the mortality rate of important organ MSOF, particularly MOFE is very high behind the severe sepsis.MOFE is in case take place, and existing treatment measure is difficult to make it reverse, and therefore prevents or alleviate the early stage organ injury of sepsis to show important especially.Early stage coagulation function promptly changes behind the sepsis, and can the systemic inflammatory response degree be closely related, effectively improve unusual coagulation function in early days after the wound, the reaction that controls inflammation, and the generation of prevention SIRS is most important.
In recent years research confirms that blood coagulation system has important function unusually in sepsis generation, evolution.During sepsis, activation of coagulation system, and promote further developing of inflammation; Inflammation also can cause activation of coagulation system, and the two influences each other, and promotes pyemic deterioration jointly.Anticoagulant system activation, then can suppress the uncontrolled inflammatory reaction, improve the prognosis of sepsis patient.Therefore, the research effect of blood coagulation system in sepsis helps further to disclose the complicated pathogenesis of sepsis, thereby new thinking is provided for pyemic treatment means and method.
In addition, can pass through the extrinsic pathway activation in the early stage blood coagulation system of sepsis.Vascular endothelial cell and mononuclear cell be at endogenous toxin rope (LPS) or inflammatory mediator, like tumor necrosis factor (TNF-a), interleukin (IL) but-the inducing of 1b under the expression tissue factor (tissue factor, TF).(activated factorVII FVIIa) forms complex, and (factor X FX), causes the blood coagulation reaction to activate the X factor for the tissue factor and the activatory VII factor.In addition; Endotheliocyte also can be expressed thrombomodulin, thrombin receptor, the von Willebrand factor (vWF) and somatomedin under the inducing of inflammatory factor, and E selects plain, iuntercellular adhesion molecule-1 (intercellular adhesion molecule-1; ICAM-1), vascular cell adhesion molecule-1 (vascular cell adhesion molecule.1; VCAM-1) etc., promote leukocyte and endothelial cell adhesion, and activated leukocyte.Research confirms, platelet at thrombin, arachidonic acid metabolite, adrenergicly induce activation down, and be attached to surfaces such as endotheliocyte, platelet, collagen protein, fibrin precipitate through film surface glycoprotein IIbPIIIa, form and assemble.Can secrete thrombin and enzyme, vaso-active substance, cytokine and other materials behind the platelet activation; Like the V factor, the VIII factor, Fibrinogen, nitric oxide, 5-hydroxy tryptamine, VEGF (vascular endothelial growth factor; VEGF) and IL-1 etc.; Thereby promote hematoblastic aggregation, and impel neutrophilic granulocyte and leukocyte recruitment, activation, increase the weight of blood vessel injury and inflammatory reaction; Platelet also can discharge expansion angiogenic substances such as prostaglandin, histamine, the damage that alleviates endotheliocyte and tissue simultaneously.
At present as anticoagulant to pyemic medicative activated protein C, TFPI, the antithrombase (AT) etc. of mainly containing.(activated protein C is an important regulatory factor of blood coagulation system APC) to activated protein C, has tangible antiinflammatory action.APC stops the thrombinogen activation through the Degradation to FX-a and FVIIIa, and it can also promote fibrinolysis through suppressing plasminogen activator inhibitor.And APC also can suppress the generation of pro-inflammatory cytokine in the endogenous toxin rope model.In addition, the sugar on the synergism factor protein S of APC can suppress E-and select element to combine with the HL, thereby shortens the systemic inflammatory response phase, reduces the activation of neutrophilic granulocyte in patient's body and the infringement that thus endotheliocyte is caused.Therefore, APC also has antiinflammatory action except possessing the anticoagulation function, is the effective way of control severe sepsis; TFPI is deactivation FVIIa/TF and FX-a specifically, thereby selectivity suppresses the activation of tissue factor approach to thrombinogen; Antithrombase (AT) is a serpin, and thrombin, FX-a, FXI-a etc. are all had deactivation, and this effect can significantly strengthen under the heparin existence condition.
Blood coagulation system and inflammatory reaction are mutually promoted, and all are that sepsis takes place, the development key factor.But single anticoagulant, process can not effectively be prevented and treated sepsis, had only simultaneously and intervened to anticoagulant and antiinflammatory link, could obtain ideal curative effect clinically.Its definite pathophysiological mechanism of coagulation disorders when being devoted to illustrate sepsis is sought new, efficacious therapy target spot, just is hopeful progressively to solve the numerous difficulties of present clinical sepsis control.
Proved already, endogenous CO during to SIRS or sepsis the release of inflammatory mediator and cytokine have effective supression effect, thereby can effectively protect cell, keep organ dysfunction.As a kind of important chemical gas courier in the body, CO can combine with sGC, and with its activation, makes GTP become cGMP.The cGMP that raises stimulates protein kinase, the phosphatase that relies on cGMP again or passes through to regulate ion channel, changes a series of biologys thereby mediate.After in zoopery, finding to suck low concentration CO, the sGC/cGMP approach is activated in vascular endothelial cell and the small intestinal endotheliocyte, causes that early stage anti-apoptosis molecule Bcl-2 raises, apoptosis front signal Bax downward modulation.Our early stage research finds that also CO brings into play anti-apoptotic effect through activating the sGC/cGMP approach.And the research of exogenous carbon monoxide intervention SIRS or Sepsis is less, mainly is because the mode that gives of exogenous CO and concentration control ratio are difficult, is unfavorable for the long-term observation experimental result.
Exogenous carbon monoxide-releasing molecules (Carbon monoxide-releasing molecules; CORMs) be new in recent years synthetic a kind of carbon monoxide complex; The method for preparing of this carbon monoxide complex and physicochemical property parameter are at the document of showing (Curr.Pharm.2003 such as Motterlini R; Detailed report is arranged 9:2525-39), and this carbon monoxide complex can be used for preparing the carbon monoxide of slow release usually.
Heparin is applied in the anticoagulant therapy and occupies an important position.Heparin still has infection, antiallergic, alleviation bronchospasm, reduces blood stickiness, microcirculation improvement, blood fat reducing and coronary artery dilator except that the organ dysfunction of alleviating damage being arranged, rebuilding the blood coagulation anticoagulant balanced action, promotes effects such as inflammation absorption.But single with heavy dose of heparin when sepsis, coagulation function is brought bigger infringement on the contrary.
Can be with described carbon monoxide-releasing molecules associating ultra micro dosage heparin, coagulation disorders when being used for treating early sepsis will improve early stage systemic inflammatory response, have very important clinical significance.
Summary of the invention
The purpose of this invention is to provide the application in preparation treatment medication for treating pyemia of carbon monoxide-releasing molecules and heparin, to satisfy the needs of clinical practice.
Medicine of the present invention; Form by preparation A and preparation B; Described preparation A comprises the carbon monoxide-releasing molecules of treating effective dose and pharmaceutically acceptable carrier; Said preparation B comprises the heparin of treating effective dose and pharmaceutically acceptable carrier; Ratio between the consumption of carbon monoxide-releasing molecules and heparin is: 6～10mg carbon monoxide-releasing molecules/100IU heparin, and preferred ratio is: 7～9mg carbon monoxide-releasing molecules/100IU heparin, most preferred ratio is: 8mg carbon monoxide-releasing molecules/100IU heparin;
Wherein: the IU of unit refers to iu;
Described carrier is selected from a kind of in DMSO or the normal saline;
Among the preparation A, the weight content of carbon monoxide-releasing molecules is 20.5mg/ml, and among the preparation B, the content of heparin is 1000IU/L;
The inventor finds through a large amount of animal experiments, and described carbon monoxide-releasing molecules is dissolved in the solvent, is placed on then in cell culture fluid or the organism; In can persistence discharge CO; So can be used as a kind of exogenous CO donor, the heparin of while Combined application ultra micro dosage, and adopt mice caecum ligation and perforation (CLP) sepsis model; Carry out early intervention; Make an experiment, find the heparin of carbon monoxide-releasing molecules Combined application ultra micro dosage, can be used as the early stage medicine of coagulation disorders when improving sepsis.
Medicine of the present invention; Preparation A can pass through the intravenously administrable approach; Preparation B can pass through the intraperitoneal administration approach, puts on the patient who needs treatment, the general 7～9mg/kg body weight/day of the dosage of carbon monoxide-releasing molecules; The dosage of heparin is generally the 100IU/kg body weight/day, specifically can be by factors such as the state of an illness decision of doctor according to patient.
Adopt the heparin of described carbon monoxide-releasing molecules Combined application ultra micro dosage to improve the sepsis coagulation disorders; Its concentration control is relatively easy and correct; Append during life-time service conveniently, reduced the consumption and the side effect thereof of heparin simultaneously, can satisfy the needs of clinical practice.The coagulation disorders when heparin that adopts described carbon monoxide-releasing molecules CORM-2 to unite ultra micro dosage improves sepsis, its concentration control is relatively easy and correct, appends during life-time service conveniently, can satisfy the needs of clinical practice.
Description of drawings
Fig. 1 is liver behind the CLP 24h, lung tissue TF protein expression (Western Blot).
The specific embodiment
Embodiment 1
The preparation of medicine:
The carbon monoxide-releasing molecules of 20.5mg is mixed with the DMSO of 1ml, and obtaining concentration content is the preparation A of 40mM, and the dosage of pressing the 8mg/kg body weight uses; With 10 times of the heparin of 20000IU/2ml and normal saline mixed dilutings, obtain the heparin solution preparation B of 1000IU/L, press the dosage use of 100IU/kg body weight.
Embodiment 2
CORM-2+ ultra micro dosage heparin is to sepsis mice WBC, PLT counting, plasminogen (PLG) and the active influence of Antithrombin III (AT-III).
Test method:
(1) animal and CLP sepsis model
Male C57BL/6 mice, in age in 6-8 week, body weight 18 ± 2 grams are raised (the dried piece material of commercialization is freely drunk water) in common lab.Laboratory animal is divided into three groups according to the table of random number method: Sham organizes (n=9), and CLP organizes (n=9) and CLP+CORM-2+ heparin group (n=9).
CLP group mice isoflurane sucks anesthesia down, and row caecum ligation and perforation are hindered injecting normal saline 1.5ml shock in the pneumoretroperitoneum; Tail vein injection CORM-2 (8mg/kg) behind the CLP+CORM-2+ heparin group mice CLP, and while lumbar injection heparin 100U/kg body weight.
Wherein: the medicine that the Sham group adopts is a normal saline, and the medicine that the CLP group adopts is a normal saline, and the medicine that the CLP+CORM-2+ heparin group adopts is the medicine of embodiment 1.(following examples are all identical)
All animals hinder excessively to suck with isoflurane in back 24 hours and make a collection of specimens after causing death.
(2) detect index
1.WBC, PLT counting:
Blood routine examination: the 1.0ml whole blood adopts Japanese SYSMEX KX-21N cellanalyzer and related reagent to measure leukocyte (WBC), platelet (PLT) with 0.1ml 15g/L EDTA-K2 anticoagulant.
2. plasminogen (PLG) and Antithrombin III (AT-III) are active detects:
Plasminogen (PLG) and Antithrombin III (AT-III) determination of activity test kit are available from Shanghai sun biotech company.
Excessively sucked the back blood sample collection that causes death with isoflurane in 24 hours behind the animal CLP.Detect WBC and PLT counting, and adopt the chromophoric substrate method to measure plasminogen (PLG) and Antithrombin III (AT-III) activity.
Statistical procedures: data are represented with mean ± standard deviation, the relatively employing t check of mean.P＜0.05 is for there being significant difference.Significance test of difference adopts the SAS6.02 statistical software.
The result is following:
1.CORM-2+ ultra micro dosage heparin to CLP after the influence of mice blood WBC, PLT counting see table 1:
Table 1
* compare P＜0.05 with matched group; △ and CLP group compare P＜0.05.
Table 1 is visible, the variation of mice blood WBC, PLT counting behind the CLP 24h.Platelet count behind the CLP (589 ± 128) reduces than normal group (750 ± 102), platelet count rising (718 ± 104) (P＜0.05) behind the use CORM-2+ ultra micro dosage heparin, and the WBC counting is not seen significant change.
2.CORM-2+ ultra micro dosage heparin to CLP after mice plasminogen (PLG) and antithrombase I II (AT-III) activity influence see table 2:
Table 2
| Divide into groups | AT?III | PLG |
| Matched group | 1.49±0.11 | 1.17±0.66 |
| ?CLP | 0.63±0.13* | 0.69±0.22* |
| The CLP+CORM-2+ heparin | 1.40±0.19△ | 0.98±0.09△ |
* compare P＜0.05 with matched group; △ and CLP group compare P＜0.05
Table 2 shows, mice plasminogen (PLG) and the active variation of Antithrombin III (AT-III) behind the CLP 24h.Antithrombin III active (0.63 ± 0.13) descends than normal group (1.49 ± 0.11) behind the CLP, active (1.40 ± 0.19) (P＜0.05) of obviously improving of Antithrombin III behind the use CORM-2+ ultra micro dosage heparin; Plasminogen behind the CLP (0.69 ± 0.22) descends than normal group (1.17 ± 0.66), and plasminogen obviously increases (0.98 ± 0.09) (P＜0.05) behind the use CORM-2+ ultra micro dosage heparin.
Embodiment 3
CORM-2+ ultra micro dosage heparin is to the influence of sepsis mice blood coagulation system and platelet aggregation
Test method:
(1) animal and CLP sepsis model
Male C57BL/6 mice, in age in 6-8 week, body weight 18 ± 2 grams are raised (the dried piece material of commercialization is freely drunk water) in common lab.Laboratory animal is divided into three groups according to the table of random number method: Sham organizes (n=9), and CLP organizes (n=9) and CLP+CORM-2+ heparin group (n=9).CLP group mice isoflurane sucks anesthesia down, and row caecum ligation and perforation are hindered injecting normal saline 1.5ml shock in the pneumoretroperitoneum; Tail vein injection CORM-2 (8mg/kg) behind the CLP+CORM-2+ heparin group mice CLP, and while lumbar injection heparin 100U/kg body weight.All animals hinder excessively to suck with isoflurane in back 24 hours and make a collection of specimens after causing death.
(2) detect index
1. sepsis mice blood coagulation system detects:
1. bleeding time: mice is through the intraperitoneal anesthesia mice behind the CLP24h, and apart from tail point 2mm place that tail is disconnected, afterbody far-end 3till immerses in 37 ℃ of saline, measures from the cross-section time to the termination of bleeding of afterbody.
2. blood coagulation system: mouse heart is got blood behind the CLP24h, and is centrifugal at once, and blood plasma mixes with the reorganization Thromboplastin in 37 ℃ of preheating 2min, record clot formation time, calculating prothrombin time.
2. the mensuration of sepsis mouse platelets aggregation capability:
Mice is through the intraperitoneal anesthesia mice behind the CLP24h, and from abdominal aortic blood, anticoagulant centrifugal (1000r/min) back obtains to be rich in hematoblastic blood plasma (PRP); Obtain plate blood plasma (PPP) when young behind the recentrifuge (2500r/min).With PPP PRP is transferred to 3 * 10
8Individual platelet/mL gets 45LPRP and mixes with 5LADP, detects its OD value.Calculate platelet aggregation rate, calculate medicine to hematoblastic gathering suppression ratio according to formula.
Assemble suppression ratio=[(contrast platelet aggregation collection one experiment platelet aggregation rate)/contrast platelet aggregation rate] * 100%
Statistical procedures: data are represented with mean ± standard deviation, the relatively employing t check of mean.P＜0.05 is for there being significant difference.Significance test of difference adopts the SAS6.02 statistical software.
The result is following:
CORM-2 associating ultra micro dosage heparin to CLP after the influence of sepsis mice blood coagulation system see table 3.
Table 3
| Divide into groups | Clotting time | (s) |
| Matched group | 68.1±30.7 | 12.8±4.23 |
| CLP | 89.9±19.8* | 13.9±5.99 |
| The CLP+CORM-2+ heparin | 180.4±46.2△ | 21.2±4.80△ |
* compare P＜0.05 with matched group; △ and CLP group compare P＜0.05
Table 3 shows that the mice bleeding time (13.9 ± 5.99) is not seen obvious prolongation than normal group (12.8 ± 4.23) behind the CLP 24h, but obviously prolongation (P＜0.05) of bleeding time (21.2 ± 4.80) behind the use CORM-2+ ultra micro dosage heparin; Clotting time of mice obviously prolongs than normal group behind the CLP 24h, and clotting time more obviously prolongs (P＜0.05) behind the use CORM-2+ ultra micro dosage heparin.
CORM-2 associating ultra micro dosage heparin to CLP after the influence of sepsis mouse platelets aggregation capability see table 4:
Table 4
| Divide into groups | Platelet aggregation rate (%) | Platelet aggregation inhibition rate (%) |
| Matched group | 55.06±20.77 | - |
| CLP | 98.33±24.65* | -43.8 |
| The CLP+CORM-2+ heparin | 62.35±19.48△ | 36.9 |
* compare P＜0.05 with matched group; △ and CLP group compare P＜0.05
Table 4 shows; Behind the CLP 24h; Platelet aggregation rate obviously improves (98.33 ± 24.65), and CORM-2 associating ultra micro dosage heparin is stronger to the anticoagulant effect, makes platelet aggregation rate drop to (62.35 ± 19.48); Significantly the inductive platelet aggregation of Trombin inhibiting (P＜0.05) is assembled suppression ratio and is reached 36.9%.
Embodiment 4
CORM-2+ ultra micro dosage heparin influences test method to what the tissue factor (TF) of sepsis Mouse Liver, lung tissue was expressed:
(1) animal and CLP sepsis model
Male C57BL/6 mice, in age in 6-8 week, body weight 18 ± 2 grams are raised (the dried piece material of commercialization is freely drunk water) in common lab.Laboratory animal is divided into three groups according to the table of random number method: Sham organizes (n=9), and CLP organizes (n=9) and CLP+CORM-2+ heparin group (n=9).CLP group mice isoflurane sucks anesthesia down, and row caecum ligation and perforation are hindered injecting normal saline 1.5ml shock in the pneumoretroperitoneum; Tail vein injection CORM-2 (8mg/kg) behind the CLP+CORM-2+ heparin group mice CLP, and while lumbar injection heparin 100U/kg body weight.All animals hinder excessively to suck with isoflurane in back 24 hours and make a collection of specimens after causing death.
(2) detect index
The tissue factor of sepsis Mouse Liver, lung tissue (TF) is expressed:
The mensuration test kit of TF is available from west, Shanghai Tang bio tech ltd.
Excessively sucked the back blood sample collection that causes death with isoflurane in 24 hours behind the animal CLP.Disconnected immediately marrow is put to death to cut open the belly and is taken out liver, lung tissue, freezing preservation after the blood sampling.Tissue specimen grinds in liquid nitrogen, with being placed on 300l buffer E [10mMHEPES (hydroxyethyl piperazine ethanesulfonic acid, HEPES pH7.9), 10mmol/LKCl; 1.5mM MgCl2,1%NP-40,0.5mM DTT (dithiothreitol, dithiothreitol, DTT); 0.5mM PMSF (phenylmethyl sulfonylfluoride, phenylmethyl sulfonylfluoride), 10g/ml aprotinin (pressing down the phthalein enzyme), 10g/mlleupeptin (leupeptin); 5% glycerol] middle ice bath homogenate, homogenate is moved in the EP pipe 4 ℃ following 3; The centrifugal 10min of 000g draws supernatant ,-80 ℃ of preservations.
TF content adopts double-antibody sandwich ABC-ELISA method to detect, and projects are operated in strict accordance with description, go up colorimetric determination at the automatic ELIASA of chameleon (Spain DIAGNOSTICGRIFOLS company).
Western blot (Western blotting): get equal protein (10g) for every group and carry out electrophoresis; Again the protein electrophorese on the PAAG is transferred to and added corresponding one anti-(rat anti-mouse TF antibody on cellulose nitrate (SG) film successively; Dilution factor is 1: 1000), two anti-(the Mus IgG of the rabbit Chinese People's Anti-Japanese Military and Political College of horseradish peroxidase-labeled, dilution factor 1: 2500) and chemiluminescence agent (Enhanced Chemiluminescence test kit, ECL); Be exposed to the x mating plate in the darkroom; Film is handled through full-automatic developing machine, and protein band is used the image analysis system analysis, sees Fig. 1.
Statistical procedures: data are represented with mean ± standard deviation, the relatively employing t check of mean.P＜0.05 is for there being significant difference.Significance test of difference adopts the SAS6.02 statistical software.
The result is following:
CORM-2+ ultra micro dosage heparin to CLP after the influence expressed of mice plasma, liver, the tissue factor (TF) of lung tissue see table 5:
Table 5
* compare P＜0.05 with matched group; △ and CLP group compare P＜0.05
Table 5 shows, blood plasma, liver, lung tissue TF protein expression (0.898 ± 0.055,1.341 ± 0.054 behind the CLP 24h; 1.044 ± 0.02) obviously increase (P＜0.05) than normal group (0.408 ± 0.042,0.714 ± 0.045,0.609 ± 0.013); The TF protein expression (0.536 ± 0.019 of internal organs behind the application CORM-2+ ultra micro dosage heparin; 0.854 ± 0.076,0.741 ± 0.012) compare obvious decline, difference significance (P＜0.05) with the CLP group.
Claims (9)
1. carbon monoxide-releasing molecules and the heparin application in preparation treatment medication for treating pyemia.
2. application according to claim 1; It is characterized in that; Said medicine is made up of preparation A and preparation B, and described preparation A comprises the carbon monoxide-releasing molecules of treating effective dose and pharmaceutically acceptable carrier; Said preparation B comprises the heparin of treating effective dose and pharmaceutically acceptable carrier, and the ratio between the consumption of carbon monoxide-releasing molecules and heparin is: 6～10mg carbon monoxide-releasing molecules/100IU heparin.
3. application according to claim 2 is characterized in that, ratio is between the consumption of carbon monoxide-releasing molecules and heparin: 7～9mg carbon monoxide-releasing molecules/100IU heparin.
4. application according to claim 3 is characterized in that, the ratio between the consumption of carbon monoxide-releasing molecules and heparin is: 8mg carbon monoxide-releasing molecules/100IU heparin.
5. according to claim 2,3 or 4 described application, it is characterized in that described carrier is selected from a kind of in DMSO or the normal saline.
6. application according to claim 5 is characterized in that, among the preparation A, the weight content of carbon monoxide-releasing molecules is 20.5mg/ml.
7. application according to claim 5 is characterized in that, among the preparation B, the content of heparin is 1000IU/L.
8. one kind is used to treat pyemic medicine; It is characterized in that; Said medicine is made up of preparation A and preparation B, and described preparation A comprises the carbon monoxide-releasing molecules of treating effective dose and pharmaceutically acceptable carrier; Said preparation B comprises the heparin of treating effective dose and pharmaceutically acceptable carrier, and the ratio between the consumption of carbon monoxide-releasing molecules and heparin is: 6～10mg carbon monoxide-releasing molecules/100IU heparin.
9. medicine according to claim 8 is characterized in that, described carrier is selected from a kind of in DMSO or the normal saline.
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