CN107550915A - A kind of Ivabradine and rolipram composition and its application in pharmacy - Google Patents
A kind of Ivabradine and rolipram composition and its application in pharmacy Download PDFInfo
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- CN107550915A CN107550915A CN201711053791.4A CN201711053791A CN107550915A CN 107550915 A CN107550915 A CN 107550915A CN 201711053791 A CN201711053791 A CN 201711053791A CN 107550915 A CN107550915 A CN 107550915A
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- rolipram
- ivabradine
- pressure
- pharmaceutical composition
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- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 title claims abstract description 74
- 229950005741 rolipram Drugs 0.000 title claims abstract description 74
- 229960003825 ivabradine Drugs 0.000 title claims abstract description 52
- ACRHBAYQBXXRTO-OAQYLSRUSA-N ivabradine Chemical compound C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 ACRHBAYQBXXRTO-OAQYLSRUSA-N 0.000 title claims abstract description 52
- 239000000203 mixture Substances 0.000 title claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 239000003814 drug Substances 0.000 claims abstract description 11
- 206010019280 Heart failures Diseases 0.000 claims abstract description 10
- 238000009472 formulation Methods 0.000 claims abstract description 9
- 238000002347 injection Methods 0.000 claims abstract description 6
- 239000007924 injection Substances 0.000 claims abstract description 6
- 229940079593 drug Drugs 0.000 claims abstract description 5
- 230000002265 prevention Effects 0.000 claims abstract description 5
- 239000000463 material Substances 0.000 claims abstract description 3
- 238000001727 in vivo Methods 0.000 description 9
- 230000002861 ventricular Effects 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 5
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 5
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 5
- 239000004041 inotropic agent Substances 0.000 description 5
- 239000002504 physiological saline solution Substances 0.000 description 5
- 230000035488 systolic blood pressure Effects 0.000 description 5
- 230000006870 function Effects 0.000 description 4
- 230000000297 inotrophic effect Effects 0.000 description 4
- 206010007559 Cardiac failure congestive Diseases 0.000 description 3
- 206010011224 Cough Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 210000001765 aortic valve Anatomy 0.000 description 3
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 3
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 3
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 3
- 210000004165 myocardium Anatomy 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000033764 rhythmic process Effects 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 2
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- ZVNYJIZDIRKMBF-UHFFFAOYSA-N Vesnarinone Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)N1CCN(C=2C=C3CCC(=O)NC3=CC=2)CC1 ZVNYJIZDIRKMBF-UHFFFAOYSA-N 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- RNLQIBCLLYYYFJ-UHFFFAOYSA-N amrinone Chemical compound N1C(=O)C(N)=CC(C=2C=CN=CC=2)=C1 RNLQIBCLLYYYFJ-UHFFFAOYSA-N 0.000 description 2
- 229960002105 amrinone Drugs 0.000 description 2
- 230000004872 arterial blood pressure Effects 0.000 description 2
- VIRRLEDAYYYTOD-YHEOSNBFSA-N colforsin daropate hydrochloride Chemical compound Cl.O[C@H]([C@@]12C)CCC(C)(C)[C@@H]1[C@H](OC(=O)CCN(C)C)[C@H](OC(C)=O)[C@]1(C)[C@]2(O)C(=O)C[C@](C)(C=C)O1 VIRRLEDAYYYTOD-YHEOSNBFSA-N 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 230000035487 diastolic blood pressure Effects 0.000 description 2
- 230000003205 diastolic effect Effects 0.000 description 2
- 229960005156 digoxin Drugs 0.000 description 2
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 2
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 210000005240 left ventricle Anatomy 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- JPAWFIIYTJQOKW-UHFFFAOYSA-N olprinone Chemical compound N1C(=O)C(C#N)=CC(C2=CN3C=CN=C3C=C2)=C1C JPAWFIIYTJQOKW-UHFFFAOYSA-N 0.000 description 2
- 229950005421 olprinone Drugs 0.000 description 2
- 230000009090 positive inotropic effect Effects 0.000 description 2
- 230000035485 pulse pressure Effects 0.000 description 2
- XMFCOYRWYYXZMY-UHFFFAOYSA-N sulmazole Chemical compound COC1=CC(S(C)=O)=CC=C1C1=NC2=NC=CC=C2N1 XMFCOYRWYYXZMY-UHFFFAOYSA-N 0.000 description 2
- 229950006153 sulmazole Drugs 0.000 description 2
- -1 thiazole piperazine ketone Chemical class 0.000 description 2
- 229950005577 vesnarinone Drugs 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- ZHEHJPNZIXHCEK-RDONPILCSA-N CCC[C@H](C)O/N=C(/C)\OC Chemical compound CCC[C@H](C)O/N=C(/C)\OC ZHEHJPNZIXHCEK-RDONPILCSA-N 0.000 description 1
- 0 CC[C@@]1CN(*)CC(C)C1 Chemical compound CC[C@@]1CN(*)CC(C)C1 0.000 description 1
- 229940122434 Calcium sensitizer Drugs 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 241000208011 Digitalis Species 0.000 description 1
- JRWZLRBJNMZMFE-UHFFFAOYSA-N Dobutamine Chemical compound C=1C=C(O)C(O)=CC=1CCNC(C)CCC1=CC=C(O)C=C1 JRWZLRBJNMZMFE-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- JAYAGJDXJIDEKI-UHFFFAOYSA-N Lanatoside C Natural products CC1OC(OC2CC3C(C4C(C5(CCC(C5(C)C(O)C4)C=4COC(=O)C=4)O)CC3)(C)CC2)CC(O)C1OC(OC1C)CC(O)C1OC(OC1C)CC(OC(C)=O)C1OC1OC(CO)C(O)C(O)C1O JAYAGJDXJIDEKI-UHFFFAOYSA-N 0.000 description 1
- JAYAGJDXJIDEKI-PTGWOZRBSA-N Lanatoside C Chemical compound O([C@H]1[C@@H](OC(C)=O)C[C@@H](O[C@@H]1C)O[C@H]1[C@@H](O)C[C@@H](O[C@@H]1C)O[C@H]1[C@@H](O)C[C@@H](O[C@@H]1C)O[C@@H]1C[C@@H]2[C@]([C@@H]3[C@H]([C@]4(CC[C@@H]([C@@]4(C)[C@H](O)C3)C=3COC(=O)C=3)O)CC2)(C)CC1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JAYAGJDXJIDEKI-PTGWOZRBSA-N 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 108091005975 Myofilaments Proteins 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- 208000010513 Stupor Diseases 0.000 description 1
- YFGQJKBUXPKSAW-ZUDKKNPISA-N [(2r,3r,4s)-6-[(2r,3s,4s)-4-hydroxy-6-[(2r,3s,4s)-4-hydroxy-6-[[(3s,9s,10s,13r,17r)-14-hydroxy-10,13-dimethyl-17-(5-oxo-2h-furan-3-yl)-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-3-yl]oxy]-2-methyloxan-3-yl]oxy-2-methyloxan-3-y Chemical compound O([C@H]1[C@@H](OC(C)=O)CC(O[C@@H]1C)O[C@H]1[C@@H](O)CC(O[C@@H]1C)O[C@H]1[C@@H](O)CC(O[C@@H]1C)O[C@@H]1CC2[C@]([C@@H]3C(C4(CC[C@@H]([C@@]4(C)CC3)C=3COC(=O)C=3)O)CC2)(C)CC1)C1O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]1O YFGQJKBUXPKSAW-ZUDKKNPISA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000009798 acute exacerbation Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000001174 ascending effect Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 229940097217 cardiac glycoside Drugs 0.000 description 1
- 239000002368 cardiac glycoside Substances 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 229940125400 channel inhibitor Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000009194 climbing Effects 0.000 description 1
- 229950005210 colforsin Drugs 0.000 description 1
- RSOZZQTUMVBTMR-XGUNBQNXSA-N colforsin daropate Chemical compound O[C@H]([C@@]12C)CCC(C)(C)[C@@H]1[C@H](OC(=O)CCN(C)C)[C@H](OC(C)=O)[C@]1(C)[C@]2(O)C(=O)C[C@](C)(C=C)O1 RSOZZQTUMVBTMR-XGUNBQNXSA-N 0.000 description 1
- 229950005198 colforsin daropate Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 229940126513 cyclase activator Drugs 0.000 description 1
- VHSBBVZJABQOSG-MRXNPFEDSA-N denopamine Chemical group C1=C(OC)C(OC)=CC=C1CCNC[C@@H](O)C1=CC=C(O)C=C1 VHSBBVZJABQOSG-MRXNPFEDSA-N 0.000 description 1
- 229950007304 denopamine Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960001089 dobutamine Drugs 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 229960002614 lanatoside c Drugs 0.000 description 1
- 210000003632 microfilament Anatomy 0.000 description 1
- 230000010016 myocardial function Effects 0.000 description 1
- 230000001777 nootropic effect Effects 0.000 description 1
- LPMXVESGRSUGHW-HBYQJFLCSA-N ouabain Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1C[C@@]2(O)CC[C@H]3[C@@]4(O)CC[C@H](C=5COC(=O)C=5)[C@@]4(C)C[C@@H](O)[C@@H]3[C@@]2(CO)[C@H](O)C1 LPMXVESGRSUGHW-HBYQJFLCSA-N 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229960002164 pimobendan Drugs 0.000 description 1
- GLBJJMFZWDBELO-UHFFFAOYSA-N pimobendane Chemical compound C1=CC(OC)=CC=C1C1=NC2=CC=C(C=3C(CC(=O)NN=3)C)C=C2N1 GLBJJMFZWDBELO-UHFFFAOYSA-N 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of pharmaceutical composition, its active component is made up of Ivabradine and rolipram, is also aided with pharmaceutically acceptable auxiliary material, and any pharmaceutically acceptable formulation is made, described formulation is injection, and discloses its application in treatment, prevention heart failure drugs are prepared.
Description
Technical field
The invention belongs to field of medicaments, is related to Ivabradine and shares application of the rolipram in pharmacy, and in particular to
Ivabradine shares application of the rolipram in treatment, prevention heart failure drugs are prepared.
Background technology
Inotropic agent is widely used in the treatment of congestive heart failure, particularly when the deterioration rank in disease
Section, by inotropic agent come to improve myocardium shrinkage function be a kind of very important treatment method.
At present, conventional inotropic agent mainly has：First, the inotropic agent that cAMP is relied on, including：1. beta-receptor is exciting
Agent：Such medicine includes dopamine, dobutamine and norepinephrine, for improving heart failure patient myocardial function barrier
Hinder the hemodynamic parameter in acute exacerbation stage.Due to the semiotic function obstacle of congestive heart failure early stage or late period occurs
(mediation signal uncoupling under beta receptor), it is relatively poor using the such congestive heart failure curative effect of beta receptor agonist treatment.Also
There is Denopamine, be new oral β1receptor partial agonist.2. the inhibitor of phosphodiesterase (PDE) III：CAMP can be direct
The shrinkage and diastolic of normal myocardium are adjusted, produces the effect of positive inotropic and positivity slackness.Such medicine passes through suppression
The degraded that PDE III reduces cAMP increases cAMP, such as Amrinone (amrinone), rolipram (Rolipram), Olprinone
And Vesnarinone (vesnarinone) etc. (olprinone).3. adenyl cyclase activator：Such medicine has Forskolin
(forskolin) and up to general sour colforsin (colforsin daropate, Adehl, NKH477) etc..2nd, cAMP is non-dependent
Inotropic agent, mainly have：1.Na+/K+-ATP enzyme inhibitors：Flowed by suppressing Na+/K+-ATP enzymes so as to increase in Ca2+,
Such as digitalis cardiac glycoside digoxin (digoxin), foxalin (digotoxin) and Lanatoside C (lantoside).2.
Calcium sensitizer：Such as Pimobendan (pimobendam), Sulmazole (sulmazole) and thiazole piperazine ketone (thiadizinone), make
For myocardium excitation-contraction coupling process, cause the transient increases of Ca2+, so as to increase the sensitiveness of myofilament or to the anti-of Ca2+
Ying Xing.Over the past several decades come, progress is achieved in terms of the research of positive inotropic medicament, then medicine with various degree
Side effect, particularly more obvious in arrhythmia cordis etc., therapeutic effect is not fully up to expectations, and room for improvement is still very big.
Ivabradine (Ivabradine) is global first selective If channel inhibitor, has been obtained early in 1992
Compound patent.In October, 2005 Europe Drug Administration office approval Ivabradine lists and is clinically used for treatment with Dou Xingxin
It is dynamic to overrun, but ARBs is not resistant to or the patients with stable angina pectoris in the presence of taboo；2015, U.S. FDA approval
Ivabradine is used for the treatment of chronic heart failure, reduces the risk that patients with heart failure is in hospital again because sb.'s illness took a turn for the worse.
The structural formula of Ivabradine is as follows：
Rolipram (Rolipram) is phosphodiesteraseⅳ inhibitor (PDE IV), and suppressing phosphodiesterase has raising
Norepinephrine, isoprel, histamine, adenosine etc. largely gather in cerebral cortex area and cerebellum region.It is existing
Show rolipram for pharmaceutical research, to the nervous system disease, such as PD, depression and anxiety disorder have certain treatment
Value, and there is nootropic effect.The structural formula of rolipram is as follows：
The positive inotropic activity for sharing rolipram to relevant Ivabradine at present has no report.
The content of the invention
The technical problems to be solved by the invention are that providing Ivabradine (Ivabradine) shares rolipram
(Rolipram) application in treatment, prevention heart failure drugs are prepared.
To reach above-mentioned purpose, technical scheme is as follows：
A kind of pharmaceutical composition, it contains Ivabradine and rolipram.
Described pharmaceutical composition, its active component are made up of Ivabradine and rolipram.
Described pharmaceutical composition, the weight ratio of its contained Ivabradine and rolipram is 1：0.5-1.5.
Described pharmaceutical composition, the weight ratio of its contained Ivabradine and rolipram is 1：1.
Described pharmaceutical composition, also it is aided with pharmaceutically acceptable auxiliary material, any pharmaceutically acceptable formulation is made.
Described pharmaceutical composition, it is characterised in that described formulation is injection.
The application of Ivabradine and rolipram as active component in treatment, prevention heart failure drugs are prepared.
Beneficial effect：Test result indicates that：Ivabradine (Ivabradine) (1mg/kg) and rolipram
(Rolipram) (1mg/kg) significantly reduces the rhythm of the heart, dramatically increases end-systolic pressure, LVEF, puts out work(after sharing, together
When Ivabradine share rolipram shorten left ventricular pressure recover 50% time and systolic pressure reply 50% time, show
Ivabradine, which shares rolipram, has the function that positive inotropic.
Brief description of the drawings
Fig. 1 is respectively that independent rolipram (1mg/kg) and Ivabradine (1mg/kg) share rolipram (1mg/kg)
The representative curve influenceed on rat in vivo left ventricular pressure-volume ring.
Fig. 2 is respectively that independent rolipram (1mg/kg) and Ivabradine (1mg/kg) share rolipram (1mg/kg)
Representative curve is acted on to rat in vivo ESPVR and EDPVR relation curve.
Fig. 3 is respectively that independent rolipram (1mg/kg) and Ivabradine (1mg/kg) share rolipram (1mg/kg)
Representative curve is influenceed on rat in vivo angiosthenia.
Embodiment
Form is described in further detail again to the above of the present invention by the following examples, but should not manage this
The scope solved as the above-mentioned theme of the present invention is only limitted to following embodiment, and all technologies for being realized based on the above of the present invention are equal
Belong to the scope of the present invention.
Embodiment 1：10g Ivabradines, 10g roliprams are mixed plus physiological saline, obtain Ivabradine and cough up
The composition of sharp Pulan, formulation are injection.
Embodiment 2：10g Ivabradines, 10g roliprams are mixed plus physiological saline, obtain Ivabradine and cough up
The composition of sharp Pulan, formulation are injection.
Embodiment 3：10g Ivabradines, 10g roliprams are mixed plus physiological saline, obtain Ivabradine and cough up
The composition of sharp Pulan, formulation are injection.
Embodiment 4：Ivabradine shares the positive inotropic activity pharmacodynamic study of rolipram
1. instrument：PowerLab polygraphs (Australian AD Instruments, model PowerLab8/
35)；Millar amplifiers (MILLAR companies of the U.S., model：735-2083Rev.F)；Millar intraventricular pressures and P-V
Conduit (model:SPR-901)
2. method：20% urethane 5ml/kg is given in healthy cleaning grade male SD rat, 250-300 grams of weight, abdominal cavity
Row anesthesia.Right carotid and left side vena jugularis externa are separated under narcosis, calibrates pressure-volume catheter pressure.She cuts down
Mine-laying fixed (1mg/kg) is dissolved in 0.2mL DMSO respectively with rolipram (1mg/kg), is slowly injected through left side vena jugularis externa
Rolipram (1mg/kg), after recording its effect 30min；Again Ivabradine (1mg/ is slowly injected through left side vena jugularis externa
Kg), the effect 30min that both continuous records share.Test and carry out body with 30% (g/100mL) salt solution and self-blood after terminating
Product calibration.The experimental result AD Instruments software analysis of Labchart 8, index include：Heart rate (heart rate,
HR), end-systolic volume (end-systolic volume, Ves), end-diastolic volume (end-diastolic volume,
Ved), end-systolic pressure (end-systolic pressure, Pes), diastasis pressure (end-diastolic
Pressure, Ped), stroke output (Stroke volume, SV), LVEF (Ejection fraction, EF), the heart
Output quantity (Cardiac output, CO), maximal ascending rate of internal pressure of left ventricle (Peak rate of rise of left
Ventricular pressure ,+dP/dtmax), bulk of left ventricle maximum climbing speed (Peak rate of rise of
Left volume ,+dP/dtmax) and put out work((Stroke work, SW), end systolic pressure-volume relations curve (End-
Systolic pressure-volume relationship, ESPVR) and diastasis pressure-PRESSURE-VOLUME RELATION curve (End-
Diastolic pressure-volume relationship, EDPVR), systolic pressure (Systolic blood pressure,
SBP), diastolic pressure (Diastolic blood pressure, DBP), pulse pressure difference (Pulse Pressure, PP), left ventricular pressure
Recover 50% time (Left ventricular pressure durations at 50%full recovery
Level, LVPD50), systolic pressure recover 50% time (Systolic blood pressure durations at 50%
Full recovery level, SBPD50) and the aortic valve closing time (Aortic valve closing time,
AVCT)。
Blank control (Control)：Independent 1mL physiological saline is slowly injected through left side vena jugularis externa.Blank control is tested
Show：Independent 1mL physiological saline is slowly injected through left side vena jugularis externa not to be influenceed the above-mentioned left ventricular pressure-PRESSURE-VOLUME RELATION of rat and moves
Mechanics parameter (n>20).
3. result：Drawn from above-mentioned experiment：Fig. 1 is respectively independent rolipram (1mg/kg) and Ivabradine (1mg/
Kg the representative curve that rolipram (1mg/kg) influences on rat in vivo left ventricular pressure-volume ring) is shared, data are shown in Table 1-
2；Fig. 2 is respectively that independent rolipram (1mg/kg) and Ivabradine (1mg/kg) share rolipram (1mg/kg) in body
Rat ESPVR and EDPVR relation curve act on representative curve, and data are shown in Table 1-2；Fig. 3 is respectively independent rolipram (1mg/
Kg) share rolipram (1mg/kg) with Ivabradine (1mg/kg) and representative curve, number are influenceed on rat in vivo angiosthenia
According to being shown in Table 3-4.
The rolipram of table 1 influences (mean ± SE, n=6) to normal rat in vivo left ventricle-volume ring
Note：Compared with blank control,*Represent P<0.05**Represent P<0.01
ESPVR:End systolic pressure-volume relations curve；EDPVR:Diastasis pressure-PRESSURE-VOLUME RELATION curve table 2 she
Cut down mine-laying and share rolipram surely to normal rat in vivo left ventricle-volume ring influence (mean ± SE, n=6)
Note：Compared with blank control,*Represent P<0.05**Represent P<0.01
ESPVR:End systolic pressure-volume relations curve；EDPVR:Diastasis pressure-PRESSURE-VOLUME RELATION curve
Influence of the rolipram of table 3 to normal rat in vivo ventricle and arterial pressure and its contraction rate
Note：Compared with blank control,*Represent P<0.05**Represent P<0.01
The Ivabradine of table 4 shares rolipram to normal rat in vivo ventricle and the shadow of arterial pressure and its contraction rate
Ring
Note：Compared with blank control,*Represent P<0.05**Represent P<0.01
Single rolipram (Rolipram) (1mg/kg) dramatically increases the rhythm of the heart (HR), Ivabradine
(Ivabradine) (1mg/kg) shares with rolipram (Rolipram) (1mg/kg) significantly reduces the rhythm of the heart (HR).
Single rolipram and Ivabradine share to dramatically increase with rolipram puts out work((SW), and she
Mine-laying is cut down to share with rolipram calmly and had more 40.6% than independent rolipram.
Single rolipram and Ivabradine share with rolipram can dramatically increase end-systolic pressure
(Pes), and Ivabradine and rolipram share and have had more 19.5% than independent rolipram.
Single rolipram and Ivabradine share with rolipram can dramatically increase LVEF (EF), and
Ivabradine shares with rolipram and has had more 13.8% than independent rolipram.
Single rolipram and Ivabradine are shared with rolipram when can significantly slow down aortic valve closing
Between (AVCT), and Ivabradine and rolipram share and have slowed down 30.7% than independent rolipram.
Single rolipram and Ivabradine share with rolipram can significantly slow down left ventricular pressure recovery
50% time (LVPD50), and Ivabradine shares with rolipram and has slowed down 22.3% than independent rolipram.
Show that Ivabradine shares rolipram and has the function that positive inotropic.
Conclusion：Illustrate that Ivabradine shares the effect of rolipram better than the effect that rolipram is used alone.
Obviously, the above embodiment of the present invention is only intended to clearly illustrate example of the present invention, and is not pair
The restriction of embodiments of the present invention.For those of ordinary skill in the field, may be used also on the basis of the above description
To make other changes in different forms.There is no necessity and possibility to exhaust all the enbodiments.And these
The obvious changes or variations that the connotation for belonging to of the invention is extended out still falls within protection scope of the present invention.
Claims (7)
1. a kind of pharmaceutical composition, it is characterised in that it contains Ivabradine and rolipram.
2. pharmaceutical composition according to claim 1, it is characterised in that its active component is by Ivabradine and rolipram
Composition.
3. pharmaceutical composition according to claim 2, it is characterised in that the weight of its contained Ivabradine and rolipram
Than for 1：0.5-1.5.
4. pharmaceutical composition according to claim 3, it is characterised in that the weight of its contained Ivabradine and rolipram
Than for 1：1.
5. pharmaceutical composition according to claim 2, it is characterised in that be also aided with pharmaceutically acceptable auxiliary material, be made and appoint
What pharmaceutically acceptable formulation.
6. pharmaceutical composition according to claim 5, it is characterised in that it is characterized in that described formulation is injection.
7. the application of Ivabradine and rolipram as active component in treatment, prevention heart failure drugs are prepared.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
| CN102284060A (en) * | 2010-06-15 | 2011-12-21 | 瑟维尔实验室 | Use of the association of a sinus node if current inhibitor and an angiotensin-converting enzyme inhibitor in the treatment of heart failure |
| CN102304088A (en) * | 2011-07-07 | 2012-01-04 | 石药集团欧意药业有限公司 | Ivabradine compound, preparation method and pharmaceutical composition thereof |
| CN102379877A (en) * | 2011-09-13 | 2012-03-21 | 南京正宽医药科技有限公司 | Western medicinal compound for preventing or treating myocardial ischemic chronic heart failure and application thereof |
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2017
- 2017-10-31 CN CN201711053791.4A patent/CN107550915A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
| CN102284060A (en) * | 2010-06-15 | 2011-12-21 | 瑟维尔实验室 | Use of the association of a sinus node if current inhibitor and an angiotensin-converting enzyme inhibitor in the treatment of heart failure |
| CN102304088A (en) * | 2011-07-07 | 2012-01-04 | 石药集团欧意药业有限公司 | Ivabradine compound, preparation method and pharmaceutical composition thereof |
| CN102379877A (en) * | 2011-09-13 | 2012-03-21 | 南京正宽医药科技有限公司 | Western medicinal compound for preventing or treating myocardial ischemic chronic heart failure and application thereof |
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| COSKUN USTA等: "Comparision of the inotropic effects of levosimendan rolipram, and dobutamine on human atrial trabeculae", 《J.CARDIOVASC PHARMACOL》 * |
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