CN107496390A - Application of the protosappanin A derivative in caused by chemotherapeutic medicines heart injury is protected - Google Patents
Application of the protosappanin A derivative in caused by chemotherapeutic medicines heart injury is protected Download PDFInfo
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- CN107496390A CN107496390A CN201710790975.2A CN201710790975A CN107496390A CN 107496390 A CN107496390 A CN 107496390A CN 201710790975 A CN201710790975 A CN 201710790975A CN 107496390 A CN107496390 A CN 107496390A
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- protosappanin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
The invention discloses application of the protosappanin A derivative in caused by chemotherapeutic medicines heart injury is protected.The chemical structural formula of described protosappanin A derivative is as shown in formula I.Effect and mechanism of the present invention to the heart damage of protosappanin A derivative protection chemotherapeutic drugs Doxorubicin induction are studied; result of study shows that the protosappanin A derivative can mitigate myocardial damage and cardiac muscle cell apoptosis and the oxidativestress damage of adriamycin induction, therefore can be used as Cardioprotective medicine.The it is proposed of the present invention provides new and effective therapy approach to treat or prevent the heart damage as caused by chemotherapeutic drug therapy.
Description
Technical field
The present invention relates to a kind of new application of protosappanin A derivative, more particularly to protosappanin A derivative is in protectionization
Treat the application in drug-induced heart injury.The invention belongs to pharmaceutical technology field.
Background technology
The incidence of disease more and more higher of tumour, the quality of life of people substantially reduce therewith at present, but as medical technology is ground
The continuous improvement studied carefully, and the extensive use of antineoplastic, the life span of tumor patient significantly extend, can it is adjoint and
Come, some tumours can directly involve cardiovascular and its accessory structure in itself, cause to seriously endanger, along with oncotherapy is dived
Cardiovascular Damage and disease of cardiovascular system have become the health problem that can not be ignored of tumor patient.
Conventional chemotherapeutics has 4 kinds, can cause different Cardiovascular Damages respectively：Endoxan belongs to alkylating agent
Class, the generation of the heart diseases such as non-specific T ripples or ST sections exception and tachyarrhythmia can be induced；Taxol, can be with
Act on micro-pipe cell and play antitumor effect, but easily induce bradycardia, myocarditis etc.；Antimetabolite fluorouracil
Angina pectoris can be caused；Different time of the anthracene nucleus medicament adriamycin after medication can induce different diseases to occur, after medication
Congestive heart failure in the transient arrhythmia cordis of a few hours and medication 1 year etc..
The adriamycin of anthracycline is the most frequently used in a few based chemotherapy medicines, its antitumous effect it has been recognised that, by with
In the treatment of clinical Several Kinds of Malignancy.However, adriamycin has obvious Cardiotoxity, in dose dependent, such as
Fruit administration time, which reaches nearly 1 year, is easy for congestive heart failure occur, and its death rate is up to 30%~50%, therefore it faces
Bed application is strictly controlled.The induced cardiotoxicity mechanism of adriamycin is also unclear, but considers it is because being formed big mostly
The super oxyradical of amount and lipid peroxidation, and cause the change of the compounds such as the related enzyme of myocardial cell energy metabolism, cause
Metabolic disorder, final myocardium cell necrosis and apoptosis, and impaired heart function caused by it occur more than medication early stage, therefore this turns into
One of problem of oncotherapy.
The dexrazoxane of American R ＆ D is proved there is myocardium protecting action for the patient of chemotherapy of tumors treatment now, its
Mechanism be mainly the medicine by the combination with iron ion so as to suppress the combination of iron ion and adriamycin, and then reduce super oxygen
Free radical is formed, and suppresses oxidative stress so as to mitigate cardiac muscle cell's denaturation and necrosis, but it is easily resistant to and is mitigating the heart
The antitumous effect of adriamycin is also reduced while dysentery.Therefore, seek a kind of new protection chemotherapeutics and cause heart
Toxicity simultaneously do not weaken chemotherapeutics antitumous effect protective agent turn into chemotherapeutics clinical practice there is an urgent need to.
Chinese medicine is developed, finds out the protection medicine of new Cardioprotective medicine, particularly caused by chemotherapeutic medicines heart damage, tool
It is with Chinese characteristics, meet China's actual conditions, be an opportunity for motherland's Chinese medicine being pushed to the world.The aboundresources of Chinese medicine, it can obtain
Property it is high, and Small side effects, toxic action are rare, cheap.Therefore find the Chinese medicine with cardioprotection or have
Composition is imitated, and furthers investigate its mechanism of action, can not only mitigate pain and the financial burden of patient, more patients is received
Chemotherapy and the life for extending patient, improve the quality of living, and have very crucial meaning.
Bush, also known as lignum sappan.For legume bush (caesalpinia sappan L.) dry duramen, mainly
Contain the compounds such as haematoxylin, brazilin, former haematoxylin.The traditional Chinese medical science thinks that it has the effect of removing heat from blood, menstruation regulating, for alleviating
Dysmenorrhoea, liver blood increase the diseases such as Sheng.Early-stage Study has confirmed that bush alcohol extract and monomer component protosappanin A have resisting transplant rejection
Effect, immunosuppressive effects are played by the activity and multiple links such as cytokine secretion that regulate and control many immunocytes.
Using the method for natural extraction protosappanin A by operating difficulties, workload is big and resulting yield is few limitation, therefore it is in section
Grind and utilization clinically also turns into a difficult point.We obtain protosappanin A using the method for chemical synthesis in follow-up study
Derivative, it was demonstrated that it has an immunosuppressive effect, and patented protection (ZL201010112431.9).In further investigated
While protosappanin A and derivative immunosupress effect, it has been found that protosappanin A derivative has protection chemotherapeutics
The effect of caused heart injury.
The content of the invention
It is an object of the invention to provide a kind of protosappanin A derivative to prepare treatment or prevention by chemotherapeutic drug therapy
Application in the medicine of caused heart damage.
The chemical structural formula of described protosappanin A derivative is as shown in formula I：
Wherein：R1It is C1-4Alkyl；R2It is C1-4Alkyl.
The specific preparation method of protosappanin A derivative shown in formula I can be found in Application No. 201010112431.9,
The record of the patent application of entitled " protosappanin A derivative and its preparation method and application ".
Wherein, it is preferred that in formula I, R1It is methyl；R2Methyl, i.e., described protosappanin A derivative for 1- (2 ',
4,4 ', 5- tetramethoxy -2- xenyls) acetone.
Wherein, it is preferred that described chemotherapeutics is adriamycin.
Wherein, it is preferred that described heart damage includes cardiac muscle cell apoptosis and fibrosis, heart function decline, brain natriuretic peptide
Concentration raises and oxidative stress rise.
Heart of the invention by the way that 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone to be used for caused by chemotherapeutic medicines
Damage, it was confirmed that protosappanin A derivative has cardioprotection, improves the work(that chemotherapeutic drugs Doxorubicin damages to myocardium toxicity
Effect, and toxic side effect is small, is a kind of Cardioprotective medicine for having very much DEVELOPMENT PROSPECT.Chinese medicine is developed, finds out new Cardioprotective
The protection medicine of medicine, particularly caused by chemotherapeutic medicines heart damage, is with Chinese characteristics, meets China's actual conditions, is motherland
Chinese medicine pushes an opportunity in the world to.The aboundresources of Chinese medicine, availability is high, and Small side effects, and toxic action is rare, valency
Lattice are cheap.Therefore Chinese medicine or active ingredient with cardioprotection are found, and furthers investigate its mechanism of action, not only may be used
Mitigate pain and the financial burden of patient, more patients is received chemotherapy and extend the life of patient, improve the quality of living,
There is very crucial meaning.
Brief description of the drawings
Fig. 1 is influence diagram of 1- (2 ', 4,4 ', the 5- tetramethoxy -2- xenyls) acetone to rat model heart function；
Wherein, Figure 1A is influence diagram of the adriamycin to rat model heart function；Figure 1B is the 1- (methoxies of 2 ', 4,4 ', 5- tetra-
Base -2- xenyls) influence diagram of the acetone low dosage to rat model heart function；Fig. 1 C be 1- (2 ', 4,4 ', 5- tetramethoxy-
2- xenyls) influence diagram of the acetone high dose to rat model heart function；
Fig. 2 is influence diagram of 1- (2 ', 4,4 ', the 5- tetramethoxy -2- xenyls) acetone to rat model cardiac index；
Fig. 3 is influence figure of 1- (2 ', 4,4 ', the 5- tetramethoxy -2- xenyls) acetone to rat model brain natriuretic peptide concentration
Show；
Fig. 4 is the influence figure that 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone changes to rat model CK-MB
Show；
Fig. 5 is the influence diagram that 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone changes to rat model cTNI；
Fig. 6 is 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) the influence figure of acetone to rat model myocardial fibrosis
Show；
Fig. 7 is 1- (2 ', 4,4 ', the 5- tetramethoxy -2- xenyls) influence of acetone to the collagen type of rat model III
Diagram；
Fig. 8 is influence of 1- (2 ', 4,4 ', the 5- tetramethoxy -2- xenyls) acetone to rat model Caspase-3 activity
Diagram；
Fig. 9 is 1- (2 ', 4,4 ', the 5- tetramethoxy -2- xenyls) influence of acetone to rat model cardiac muscle cell apoptosis
Diagram；
Figure 10 is 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone to rat model Bcl-2mRNA expressions
Influence diagram；
Figure 11 is the influence diagram that 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone changes to rat model SOD；
Figure 12 is the influence diagram that 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone changes to rat model MDA；
Figure 13 is influence diagram of 1- (2 ', 4,4 ', the 5- tetramethoxy -2- xenyls) acetone to rat model blood routine；
Figure 14 is influence diagram of 1- (2 ', 4,4 ', the 5- tetramethoxy -2- xenyls) acetone to rat model blood biochemistry.
Embodiment
The forgoing and additional technical features and advantages are described in more detail with reference to embodiments.Should
Understand, embodiments discussed below is only that the preferred embodiment of the present invention is described, not to the present invention's
Scope is defined, on the premise of design spirit of the present invention is not departed from, technology of the those of ordinary skill in the art to the present invention
The various modifications and improvement that scheme is made, it all should fall into the protection domain of claims of the present invention determination.
The 1- of embodiment 1 (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone changes to adriamycin processing Cardiac Function in Rat
Kind effect
Experimental method：
1. induced by adriamycin in rat induces the foundation of myocardial injury models
After adriamycin is 1mg/ml concentration with normal saline dilution, rats by intraperitoneal injection adriamycin makes its dosage be
2.5mg/kg/w, myocardial injury models can be obtained after 6 weeks.
2. animal packet and administration
Animal pattern gives different medicine gavages, is randomly divided into three groups：(1) control group, physiological saline gavage；(2) change
Compound low dose group：Give 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone (5mg/kg/w) gavage；(3) compound
High dose group：Give 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone (25mg/kg/w) gavage.Above each group animal
By adriamycin processing the previous day administration.
3. the observation of general state after administration
Observation include to Mental development situation, diet and the active situation of control group and compound rats, changes of weight,
The observation for phenomena such as whether stool and urine character is normal.
4. color ultrasound and echocardiogram：Ultrasonic testing model rat (6 weeks), 10% chloral hydrate anesthesia, pareordia preserved skin,
Dorsal position, using multifunction supersonic diagnostic equipment, popped one's head in (frequency probe 11.0MHz) detection with 10S.The left room major axis of parasternal is taken to cut
Face, left room end systolic diameter (LVESD), LVED (LVEDD), left ventricular ejection fraction are measured respectively
(EF)。
5. cardiac index calculates：Weigh and keep a record immediately after rat color ultrasound, dissection immediately takes out heart and weighs heart
Weight, wet heart weight/rat body weight, evaluation.
6 brain natriuretic peptides monitor:Rat abdominal cavity is quickly splitted after the completion of color ultrasound, isolates inferior caval vein, uniform speed slow
Draw blood, centrifugation 5min, collect supernatant with 4 DEG C, 4000rpm after standing 20min in the solidifying pipe of injection rush and saved backup in -80 DEG C.Inspection
Operated during survey in strict accordance with BNP kit steps.
Experimental result is as shown in Figure 1, 2, 3, it was demonstrated that 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone alleviates Ah
Impaired heart function degree caused by mycin, the concentration of brain natriuretic peptide is reduced, there is significant difference compared with control group.Prove 1-
(2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone is effective Cardioprotective medicine, can be obviously improved adriamycin induction
Myocardium toxicity infringement.
The 1- of embodiment 2 (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone is to rat myocardium from injury and the shadow of fibrosis
Ring
Foundation, animal packet and the administration of induced by adriamycin in rat induction myocardial injury models are the same as embodiment 1.
Testing index and method：
1. the detection of myocardium enzyme and troponin：It is administered after 6 weeks and three groups of rats is handled immediately, plucks eyeball and take blood,
Operating method and step are carried out by myocardium enzyme and troponin kit specification.
2.Masson is dyed：Experiment flow is paraffin section de-waxing, brazilwood extract dyeing, phosphomolybdic acid aqueous solution differentiation 3-
5min, glacial acetic acid aqueous solution is dipped in, be dehydrated, dimethylbenzene is transparent, resinene mounting.
The detection of III collagen type：Rat is handled immediately after being administered 6 weeks, rat cardiac ventricular is extracted with Trizol methods
Muscular tissue total serum IgE, operation technique are carried out according to kit specification, and response procedures are first pre- hot 95 DEG C, 1min；Repeat 40
Secondary 95 DEG C, 15s is adjusted to 58 DEG C, 20s, then is adjusted to 72 DEG C, 45s；Solubility curve is 60 DEG C to 95 DEG C, increases by 1 DEG C every 20s, reaction
Thing includes the μ l of 2 × qPCR mixed liquors 5,2.5 μm 1 of primer working solution μ l, qPCR template 1 μ l, the μ l of distilled water 2.8, amplimer：
5'-TGTCCACAGCCTTCTACACCT-3'(sense primers),
5'-TAGCCACCCATTCCTCCG-3'(anti-sense primers).
Analysis result, experimental result as shown in FIG. 4,5,6, 7, show 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls)
Acetone can mitigate myocardial damage and the fibrosis of adriamycin induction, and its effect is in dose dependent.
The 1- of embodiment 3 (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone suppresses adriamycin inducing cardiomyocytes apoptosis
Effect
Experimental method:
(1) myocardial cells culture：Core tip, cleaned 3 times with the D-Hank ' s liquid of precooling in advance, heart is cut into about 1
Cubic millimeter size；Cardiac muscular tissue is handled with pancreatin (0.0625%), temperature is 37 DEG C, is carried out by several times, the time is 5min × 5
It is secondary, it is further added by 1 minute, is repeated 5 times, by that analogy, until being added to 8 minutes, supernatant is abandoned in natural sedimentation after digestion first, is connect down
Supernatant is left and taken after carrying out each natural sedimentation；The supernatant collected adds same volume DMEM nutrient solutions, and piping and druming mixes, and action is light
It is soft, 1 000r/min centrifugation 10min, it is repeated 3 times.Cell is divided into three groups, 1. adriamycin treatment group：ADR is added, it is final concentration of
8 μm of ol/L 2. compound low dose groups：Adriamycin processing adds 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone simultaneously
(5nM) 3. compound high dose group：Adriamycin processing adds 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone simultaneously
(25nM), stimulate 12h, micro- sem observation cellular morphology.
(2) Level of Apoptosis detects：Culture medium is removed after above-mentioned three groups of 12h, with PBS 1 or 2 times, concrete operations
Step is carried out by Caspase-3 Activity Assay Kits specification, and each administration group absorbance A is determined under λ=405nm, calculates A
(administration group)/A (blank group), evaluation Caspase-3 activity.
(3) flow cytometer detection Apoptosis：The cell of adherent growth need to be digested and received with 0.25% pancreatin without EDTA
Collect, under room temperature condition, 2000r/min is centrifuged 5~10 minutes, collects cell, adds the PBS (4 DEG C) of precooling, and cell is resuspended one
Secondary, 2000rpm is centrifuged 5 to 10 minutes, washs cell, adds 300 μ L 1 × Binding Buffer suspension cells, adds 5 μ L
Annexin V-FITC mix after, lucifuge is incubated at room temperature 15 minutes, and 5 μ L PI dyeing, upper machine are added within 5 minutes before upper machine
Before, the 1 × Binding Buffer for adding 200 μ L are detected.
(4) PCR detects apoptosis-related genes：(Bcl-2)
By RNA extracts kits specification extraction cardiac muscular tissue total serum IgE.Reverse transcription total serum IgE is by M-M LV reverse transcriptases
Specification operates.After 70 DEG C of 10min inactivation M-M LV reverse transcriptases, 100 μ L are diluted to PCR water.5 μ L reverse transcription products are taken to make
Enter performing PCR amplification for template.Primer sequence is：5 ' TCCATT ATA AGC TGT CACAG 3 ' (sense primer)；5′
GAAGAGTTCCTCCACCAC 3 ' (anti-sense primer).PCR reaction cumulative volumes are 25 μ L：Reverse transcription product 5 μ L's, 10pmol is upper
Trip and each μ L of 2 μ L, 5mmol/LdN TP 1 of anti-sense primer, 10 × reaction buffer 2.5 μ L, 25mmol/L MgCl21.5 μ L,
The μ L of Taq archaeal dna polymerases 1U, PCR water 10.75.PCR amplification procedures：94 DEG C, 50 DEG C and 72 DEG C each 1min, are repeated 1 times；94 DEG C,
55 DEG C and 72 DEG C of each 1min, repeat this step 35 time；72 DEG C, 15min.Analysis result simultaneously calculates.
As shown in Figure 8,9, 10, the result shows 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone to experimental result
The effect of adriamycin inducing cardiomyocytes apoptosis is significantly inhibited, further demonstrate that the Cardioprotective of such compound is made
With.
The 1- of embodiment 4 (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone suppresses cardiac muscle cell's oxygen caused by adriamycin
Change stress level to increase
Foundation, animal packet and the administration of induced by adriamycin in rat induction myocardial injury models are the same as embodiment 1.
Testing index and method：
The detection of SOD, MDA content：After being administered 6 weeks, after putting to death rat, heart tissue about 0.5g, physiological saline cleaning are taken
To wash blood off, wiped with filter paper dry, weigh weight and simultaneously shred measured heart tissue block as early as possible.It is organized in homogenizer and fully grinds
It is broken.10% tissue is homogenized and centrifuges 3 000r/min in refrigerated centrifuge, 10 arrive 15min.Supernatant is collected, is determined in heart
MDA, SOD content.Often step operation is carried out according to kit specification.
Experimental result is as shown in Figure 11,12：Kit measurement MDA and SOD content, using 1- (2 ', 4,4 ', 5- tetra-
Methoxyl group -2- xenyls) the acetone content of the latter two substantially reduces, it was demonstrated that 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls)
Oxidative stress caused by acetone adriamycin, which improves, certain inhibitory action.
The toxic side effect of the 1- of embodiment 5 (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone
Foundation, animal packet and the administration of induced by adriamycin in rat induction myocardial injury models are the same as embodiment 1.
Experimental method：Observation is included to the state of mind of control group and compound rats, diet and active situation, body weight
Change, the observation for phenomena such as whether stool and urine character is normal.Anaesthetized after 7 days, open abdomen, inferior caval vein blood sampling 4-5ml, it is normal to enter promoting circulation of blood
Rule and biochemical analysis, take liver and kidney to do pathology detection, specify the work of 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone
With.
Experimental result is as shown in Figure 13,14：Using rat serum after 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone
Routine and biochemical indicator are without significantly changing.And 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone liver-kidney diseases reason is without significantly
Change.
Claims (4)
1. protosappanin A derivative answering in the medicine for treating or preventing the heart damage as caused by chemotherapeutic drug therapy is prepared
With the chemical structural formula of described protosappanin A derivative is as shown in formula I：
Wherein：R1It is C1-4Alkyl；R2It is C1-4Alkyl.
2. application as claimed in claim 1, it is characterised in that in formula I, R1It is methyl；R2Methyl, i.e., described former Soviet Union
Lignin A derivatives are 1- (2 ', 4,4 ', 5- tetramethoxy -2- xenyls) acetone.
3. application as claimed in claim 1, it is characterised in that described chemotherapeutics is adriamycin.
4. application as claimed in claim 1, it is characterised in that described heart damage include cardiac muscle cell apoptosis and fibrosis,
Heart function declines, the rise of brain natriuretic peptide concentration and oxidative stress raise.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710790975.2A CN107496390B (en) | 2017-09-05 | 2017-09-05 | Application of hematoxylin A derivative in protecting heart damage caused by chemotherapeutic drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710790975.2A CN107496390B (en) | 2017-09-05 | 2017-09-05 | Application of hematoxylin A derivative in protecting heart damage caused by chemotherapeutic drugs |
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| CN107496390B CN107496390B (en) | 2020-10-27 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109288835A (en) * | 2018-08-08 | 2019-02-01 | 北京大学 | Application of the compound in the drug of preparation treatment acute pulmonary embolism |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102146026A (en) * | 2010-02-10 | 2011-08-10 | 哈尔滨医科大学 | Protosappanin A derivative and preparation method and application thereof |
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2017
- 2017-09-05 CN CN201710790975.2A patent/CN107496390B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102146026A (en) * | 2010-02-10 | 2011-08-10 | 哈尔滨医科大学 | Protosappanin A derivative and preparation method and application thereof |
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| Title |
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| JIAN WU 等: "Protosappanin A induces immunosuppression of rats heart transplantation targeting T cells in grafts via NF-κB pathway", 《NAUNYN-SCHMIEDEBERG"S ARCHIVES OF PHARMACOLOGY》 * |
| MAOMAO ZHANG 等: "The immunosuppressant Protosappanin A diminished recipient T cell migration into allograft via inhibition of IP-10 in rat heart transplant", 《PLOS ONE》 * |
| 吴健 等: "苏木醇提物抗大鼠心脏移植排斥反应有效成分分析", 《哈尔滨医科大学学报》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109288835A (en) * | 2018-08-08 | 2019-02-01 | 北京大学 | Application of the compound in the drug of preparation treatment acute pulmonary embolism |
| CN109288835B (en) * | 2018-08-08 | 2020-09-25 | 北京大学 | Application of compound in preparation of medicine for treating acute pulmonary embolism |
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