CN102218134A - L-arginine-glucose-insulin-potassium chloride composition and application thereof - Google Patents
L-arginine-glucose-insulin-potassium chloride composition and application thereof Download PDFInfo
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- CN102218134A CN102218134A CN2011101440096A CN201110144009A CN102218134A CN 102218134 A CN102218134 A CN 102218134A CN 2011101440096 A CN2011101440096 A CN 2011101440096A CN 201110144009 A CN201110144009 A CN 201110144009A CN 102218134 A CN102218134 A CN 102218134A
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Abstract
The invention discloses an L-arginine-glucose-insulin-potassium chloride composition which uses water as a solvent and comprises 5-10 wt% glucose, 20-50 IU/L insulin, 40-100 mmol/L potassium chloride and 1-50 g/L L-arginine. The L-arginine-glucose-insulin-potassium chloride composition supplements exogenous L-Arg, and activates the cardiovascular system eNOS through the glucose-insulin-potassium chloride, thereby enhancing the generation of endogenous NO, displaying the heart protective action, reducing the myocardial infarction and promoting the recovery of cardiac function. The composition can be used for preparing medicaments for resisting ischemic cardiac trauma or heart failure.
Description
Technical field
The invention belongs to the Prevention Technique field of ischemic heart desease, particularly L-arginine-glucose-insulin-potassium chloride compositions and application thereof.
Background technology
Ischemic heart desease is to cause the uneven cardiac damage that causes between coronary flow and the myocardium demand owing to coronary artery circulation changes.Promptly original or do not have on the basis that atheromatous plaque forms at heart coronary artery, because it is narrow or inaccessible that coronary lumen takes place for the spasm of arteria coronaria or the thrombosis that endothelial injury causes, conflict between the need blood of the blood supply of arteria coronaria and cardiac muscle, cause angina pectoris attacks or myocardial infarction.The sickness rate of Epidemiological study ischemic heart desease increases year by year, along with this disease of change of people life style becomes harm humans life and health important diseases day by day.
The early stage vascular endothelium dysfunction of myocardial ischemia causes that endothelium generates nitric oxide (NO) and reduces, and the minimizing of NO content has increased the weight of myocardium infringement.Consider that at present the application vasodilator improves myocardial ischemia following several method is generally arranged:
1) nitroglycerin administration: oral nitroglycerin, there be significantly " first pass effect ", bioavailability is extremely low, so the non-constant of oral nitroglycerin preparation effect.Sublingual administration can be absorbed by oral mucosa rapidly, dosage expansion of veins system not only during greater than 40 μ g/min, and resistance vessel is also worked to tremulous pulse.The prevention angina pectoris attacks also can use slow releasing agent or medicine hymeniderm skin sticks.
2) sorbide nitrate administration: tablet, aerosol, slow releasing agent, ointment, intravenous injection are arranged.This medicine has slow releasing preparation can reduce the medication number of times equally.In addition, sorbide nitrate oral spray, medicine are sprayed on the cheek mucosa of oral cavity, can absorb rapidly, and the medicinal liquid of whenever pushing 2 ejections is equivalent to contain the effect of nitroglycerin 0.3mg or sorbide nitrate 5mg.
Long-term continuous application nitrate esters medicine can produce drug resistance and drug dependence.Body only is a part to the drug resistance of mononitrate ester healer deposits yields, and it is still effective to increase dosage; This drug resistance can disappear after drug withdrawal a few hours, used this medicine once more and still can play a role again.Produce chemical sproof mechanism and mainly be because the sulfydryl receptor of vascular smooth muscle cell film reduces, cause that in the smooth muscle cell the synthetic minimizing of NO and cGMP causes.Body can produce drug dependence to nitrate esters medicine, if drug withdrawal suddenly can produce knock-on property coronary vasospasm, causes drug withdrawal syndrome, shows as violent chest pain, and myocardial infarction even sudden death can take place.So the life-time service nitrate esters medicine, unsuitable drug withdrawal suddenly.
3) Covera-HS administration: preparation commonly used has nifedipine, diltiazem and verapamil.Nifedipine is strong to the vascular smooth muscle effect, and energy coronary artery dilator and peripheral blood vessel do not have obvious influence to conducting system of heart.Blood vessel dilating brings high blood pressure down, and the reflexive sympathetic activation that causes is enough to offset its negative inotropic action to cardiac muscle, even shows as positive inotropic action, thereby improves the ischemic region myocardium shrinkage function.Diltiazem props up systemic vascular to coronary artery and side thereof all stronger dilating effect, can bring high blood pressure down, decreased heart rate and reduce myocardial oxygen consumption, and cardiac muscle is had direct negativity muscular strength and negative chronotropic action, can prolong the conduction time of sinuatrial node and atrioventricular node.Verapamil can be expanded peripheral blood vessel, reduces vascular resistance, to dilating effect coronarius a little less than, but can suppress the coronary vasospasm that causes because of sympathetic activation or ergometrine.Can directly suppress cardiac muscle and produce negative inotropic action, suppress the irritability and the conduction function of sinuatrial node and atrioventricular node simultaneously.
Glucose-insulin-potassium chloride (GIK) is used for the long history that auxiliary treatment ischemic heart desease (IHD) has year surplus in the of 40 as the cellular energy metabolism regulators.GIK provides more multipotency (glucose) to ischemic myocardium, and suppresses ischemic myocardial cells by insulin and absorb and utilize free fatty acid, promote the myocardial cell picked-up and utilize glucose, finally promotes the functional rehabilitation of ischemic myocardium.In recent years clinical trial confirms that repeatedly GIK can significantly reduce acute myocardial infarction (AMI) mortality in said patients; Recently insulin (a kind of classical hormone) Its Mechanisms is shown, insulin is except that promoting cellular energy metabolism and protein synthesis, also but active cell " existence signal (survival signaling) " system resists damage, anti-apoptosis, promotes cytothesis and existence.
The early stage GIK injection that uses can reduce patient's mortality rate significantly in the treatment ischemic heart desease, reduces infarcted myocardium area and cardiac cellular apoptosis.Wherein important mechanism is that the insulin among the GIK is protected heart, anti-cardiac damage by activating myocardial cell existence signal pathway " AKt-eNOS-NO ".The GIK that discovers in the past can also promote the activity of eNOS synthase simultaneously, strengthens the protective effect of heart.
Summary of the invention
The problem that the present invention solves is to provide a kind of L-arginine-glucose-insulin-potassium chloride compositions and application thereof, by the NO in the middle of the increase serum, alleviate the infringement of myocardial cell, reduce myocardial damage, heart apoptosis and heart dysfunction that ischemic heart desease causes.
The present invention is achieved through the following technical solutions:
L-arginine-glucose-insulin-potassium chloride compositions is characterized in that, as solvent, comprising mass concentration is 5～10% glucose, the insulin of 25～50IU/L, the potassium chloride of 40～100mmol/L and the L-arginine of 1～50g/L with water.
Described L-arginine-glucose-insulin-potassium chloride compositions is applied to the preparation of ischemia resisting heart and injury or anti-heart failure medicine.
Described L-arginine-glucose-insulin-potassium chloride compositions is applied to the preparation of the curative drug or the protective medicine of ischemia resisting heart and injury.
Compared with prior art, the present invention has following beneficial technical effects:
Early stage at ischemic heart desease (myocardial ischemia), vascular endothelium dysfunction causes that endothelium generates nitric oxide (NO) and reduces, and the minimizing of NO content has further increased the weight of myocardium infringement.In order to alleviate the infringement of the myocardial cell that causes owing to ischemia, just be necessary very much the NO in supplemental blood and the heart.And the function of nitricoxide synthase (eNOS) and substrate L-arginine (L-Arg) content of its effect are depended in the generation of NO in the body.The content of the substrate L-arginine of the NO among the normal human is metastable, and the L-Arg during myocardial ischemia in vascular endothelial cell and the myocardial cell is exhausted in a large number.
L-arginine-glucose provided by the invention-insulin-potassium chloride compositions, be based on the activation of eNOs and the amount of NO generation the protection heart is played important biological effect, the L-Arg of one side supplemented with exogenous, the L-Arg that is exhausted in a large number in vascular endothelial cell and the myocardial cell when being increased in myocardial ischemia; On the other hand, activate eNOS, so that providing of NO to be provided by glucose-insulin-potassium chloride.L-arginine-glucose-insulin-potassium chloride compositions is set about from two aspects like this, activate eNOs and replenish enough NO and generate substrate L-Arg, thereby the NO in the middle of the increase serum, the physiological function that damaged myocardium is brought into normal play again, thereby reduce the infringement of cardiac muscle in ischemia, reduce the infarcted hearts area.
The rat model of myocardial ischemia can increase the central NO of serum significantly, reduce the infarcted hearts area after perfusion L-arginine-glucose-insulin-potassium chloride compositions; The result shows that L-arginine-glucose-insulin-potassium chloride compositions can be applicable to the treatment and the defence of ischemia resisting heart and injury disease, and has auxiliary anti-heart failure effect concurrently.
Description of drawings
Fig. 1 is the interpretation of result figure of the content of the total NO of heart of dabbling different groups again behind the ischemia;
Fig. 2 is the interpretation of result figure of the infarct size of dabbling different groups/ischemic areas value again behind the ischemia.
The specific embodiment
L-arginine-glucose provided by the invention-insulin-potassium chloride compositions, the L-Arg of one side supplemented with exogenous, the L-Arg that is exhausted in a large number in vascular endothelial cell and the myocardial cell when being increased in myocardial ischemia; On the other hand, activate cardiovascular system eNOS, strengthen endogenous NO and produce by GIK; to strengthen providing of NO, performance cardioprotection, the physiological function that damaged myocardium is brought into normal play again; thereby reduce the infringement of cardiac muscle in ischemia, reduce the infarcted hearts area, promote cardiac function to recover.The present invention is described in further detail below in conjunction with the perfusion of L-arginine-glucose-insulin-potassium chloride preparation of compositions and rat ischemia model, and the explanation of the invention is not limited.
1, L-arginine-glucose-insulin-potassium chloride preparation of compositions:
With the aseptic double-distilled water is solvent, at first prepares glucose-insulin-Klorvess Liquid: mass concentration is 5～10% glucose, the insulin of 25～50IU/L and the potassium chloride of 40～100mmol/L.
It is 20% mother solution that L-arginine is set to mass concentration, then the L-arginine mother solution is joined in glucose-insulin-Klorvess Liquid, makes that the final concentration of L-arginine is 1～50g/L.
2, L-arginine-glucose-insulin-potassium chloride compositions is to the protective effect of Ischemic Heart
2.1 rats with myocardial ischemia Preparation of model
Select the male rat of body weight 200～240g for use, random packet: pseudo-operation group (Sham), myocardial ischemia (30 minutes) pours into normal saline group (MI/R+Saline), myocardial ischemia-reperfusion L-Arg group (MI/R+L-Arg), myocardial ischemia-reperfusion GIK group (MI/R+GIK) and myocardial ischemia L-Arg+GIK group (MI/R+L-Arg+GIK) again, 6～10 every group again.
Myocardial infarction and ischemia model is used key instrument: animal artificial respirator, bio signal record analysis system and toy micro-injection pump.
Being treated to of rats with myocardial ischemia model:
Earlier with rat with 3% pentobarbital sodium (30mg/Kg) intraperitoneal injection of anesthesia, it is fixing to lie on the back, cervical region medisection skin, intubate is kept eupnea.Open the thoracic cavity at the most tangible the 4th intercostal of heartbeat, strut rib, tear the left auricle and the left ventricle surface that expose heart behind the pericardium with eye speculum.
Below left auricle, be sign, pass myocardium top layer with 5-0 noinvasive sewing needle in 2mm place, left auricle root below, at pulmonary conus branch pin with heart surface great cardiac vein trunk; Observe electrocardiogram, treat that its recovery was stablized after 15 minutes to do a slip-knot with the ligation ramus descendens anterior arteriae coronariae sinistrae, leading with electrocardiogram I, II, ST section back of a bow sample is upwards raised, heart surface respective regions colour-darkening shows the ischemia success; Untwisting binding after 30 minutes, reduction in ST segment depression more than 1/2, heart surface redden and show that cardiac muscular tissue recovers perfusion again.Layer-by-layer suture rib, muscle and skin again after perfusion reduce ventilation gradually, and rat is pulled out tracheal intubation after autonomous respiration is arranged.The capable intubation of rat femoral vein is set up venous channel.
The operation of pseudo-operation group rat is identical, and sewing needle is passed the ramus descendens anterior arteriae coronariae sinistrae below, but not ligation.
2.2 perfusion again behind the ischemia
3 groups of ischemia-reperfusion administration group, giving vein micro-injection L-Arg (1mg/Kg/min) again between flush phase respectively, glucose-insulin-potassium chloride injection (glucose: 5%, insulin: 50IU/L, potassium chloride: 100mmol/L, 0.125ml/Kg/min), L-Arg+ glucose-insulin-potassium chloride group (L-Arg 1mg/Kg/min+ glucose: 5%, insulin: 50IU/L, potassium chloride: 100mmol/L, 0.125ml/Kg/min) pseudo-operation group and ischemia-reperfusion normal saline group give normal saline solution injection (0.125ml/Kg/min).
For the ease of observing of the influence of L-arginine-glucose-insulin-potassium chloride compositions, use Azo-Blue (Evan ' s Blue) and chlorinated triphenyl nitrogen azoles (TIC) to dye to myocardium of left ventricle to the Ischemic Heart infarct size.Concrete grammar is as follows: after pouring into 3 hours behind the ischemia, ligation coronary artery once more, entad indoor quick injection 2%Evan ' s Blue, cut heart from the heart root, cut off atrium, right ventricle, 4 ℃ of normal saline rinsings are cut into 6 thick ring-type thin slices of 1～2mm perpendicular to long axis of heart, and the dyeing of 1%TIC phosphate solution is 15 minutes in 37 ℃ of water-baths.Normal myocardium is blue, and infarcted region is a white, and ischemia not infarcted region is red.
2.3 L-arginine-glucose-insulin-potassium chloride compositions is to the influence of ischemic myocardium
2.3.1 the influence of the content of the total NO of heart
The NO chemical property is active, and metabolism is converted into NO very soon in vivo
2-And NO
3-, NO
2-Can further be converted into NO
3-The restore nitrification enzyme spcificity is with NO
3-Be reduced to NO
2-, measure its concentration by the colour developing depth.It is dirty to core, and utilizes the restore nitrification enzyme process to measure the content of the total NO of heart.Organize pre-treatment: tissue homogenate is 10%, and centrifugal 1000r/min centrifugal 5 minutes, gets supernatant and measures.The measurement of NO uses Nanjing to build up company's kit measurement.
The analysis chart of drawing according to the testing result of the content of the total NO of heart as shown in Figure 1, the NO content of pseudo-as can be seen operation group is the highest, ischemia-reperfusion normal saline group (matched group) NO content is minimum, ischemia-reperfusion L-Arg and ischemia-reperfusion GIK help the raising of NO content, have remarkable difference with matched group and (compare * P＜0.05 with matched group, n=7); And the raising of ischemia-reperfusion L-Arg+GIK group NO content is more obvious, has more remarkable difference with matched group (to compare * * P＜0.01 with matched group, n=7); Also have remarkable difference with preceding two groups: compare with ischemia-reperfusion L-Arg group, #P＜0.05 (n=7), GIK compares with ischemia-reperfusion, § P＜0.05 (n=7).
The supply of heart NO reduced the infringement of cardiac muscle in ischemia when this explanation perfusion L-Arg+GIK compositions can improve ischemia more significantly.
2.3.2 influence to the Ischemic Heart infarct size
The Ischemic Heart infarct size that the dyeing of Azo-Blue and chlorinated triphenyl nitrogen azoles detects and the interpretation of result figure of ischemic areas ratio are as shown in Figure 2, the infarct size of pseudo-as can be seen operation group/ischemic areas value is minimum, infarct size/the ischemic areas value is the highest for ischemia-reperfusion normal saline group (matched group), ischemia-reperfusion L-Arg and ischemia-reperfusion GIK help the minimizing of infarct size, and ischemia-reperfusion GIK has remarkable difference (comparing * P＜0.05 with matched group) with matched group; And ischemia-reperfusion L-Arg+GIK group is more obvious to the minimizing of infarct size, has more remarkable difference (comparing * * P＜0.01 with matched group) with matched group.
The minimizing of heart infarct size reduced the infringement of cardiac muscle in ischemia when this explanation perfusion L-Arg+GIK compositions can reduce ischemia more significantly.
2.3.3 influence to CK (creatine kinase) and MPO (myeloperoxidase)
Creatine kinase in the tissue (CK) extensively is present in the various tissues, and is relevant with the regeneration of adenosine triphosphate (ATP), and the function of this enzyme is to keep intracellular adenosine triphosphate concentration on physiological level.CK can be released into blood from cell when cell is impaired, thereby the height of blood plasma or serum CK level can be used to reflect the degree of cell, tissue damaged, and serum CK raises during as myocardial damage.The most important meaning that clinical use blood plasma, serum CK are measured is the diagnosing acute myocardial infarction.
MPO is a kind of mark of neutrophilic granulocyte activation, discharges increase as inflammatory mediator MPO when cell is impaired.Organize the level of MPO can reflect the heart ischemia reperfusion lesion center muscular tissue extent of damage.
Utilize the enzymatic activity detection method to detect in the blood plasma myeloperoxidase in the creatine kinase and heart tissue, concrete result is as shown in table 1.
Table 1L-Arg+GIK compositions is to the influence of the MPO of Plasma CK and ischemic myocardium
(compared?with?MI/R±saline，*P＜0.05，**P＜0.01)(n＝7)
As can be seen from Table 1, the CK content that goes out pseudo-operation group is minimum, and ischemia-reperfusion normal saline group (matched group) CK content is the highest, and the CK content of ischemia-reperfusion L-Arg and ischemia-reperfusion GIK group decreases, have remarkable difference with matched group and (compare * P＜0.05 with matched group, n=7); And the reduction of ischemia-reperfusion L-Arg+GIK group CK content is more obvious, has more remarkable difference with matched group and (compares * * P＜0.01 with matched group, n=7).This shows that ischemia-reperfusion L-Arg+GIK can effectively reduce the release of CK, reduces the degree of cell, tissue damaged.
It can also be seen that from table 1, the MPO content that goes out pseudo-operation group is minimum, ischemia-reperfusion normal saline group (matched group) MPO content is the highest, the MPO content of ischemia-reperfusion L-Arg and ischemia-reperfusion GIK group decreases, have remarkable difference with matched group and (compare * P＜0.01 with matched group, n=7); And ischemia-reperfusion L-Arg+GIK group MPO content reduce with matched group have equally remarkable difference (compare * * P＜0.01 with matched group, n=7), but MPO content than preceding two groups still be low.This shows that ischemia-reperfusion L-Arg+GIK can effectively reduce the release of MPO, reduces the impaired degree of cardiac muscular tissue.
Comprehensive above testing result, show perfusion L-arginine-glucose-insulin-potassium chloride compositions, when heart ischemia, can increase the NO in the middle of the serum, reduce the infarcted hearts area, reduce the infringement of cardiac muscle in ischemia, can be applicable to the treatment and the defence of ischemia resisting heart and injury disease.
Claims (3)
1. L-arginine-glucose-insulin-potassium chloride compositions, it is characterized in that, as solvent, comprising mass concentration is 5～10% glucose, the insulin of 25～50IU/L, the potassium chloride of 40～100mmol/L and the L-arginine of 1～50g/L with water.
2. the described L-arginine-glucose of claim 1-insulin-potassium chloride compositions is applied to the preparation of ischemia resisting heart and injury or anti-heart failure medicine.
3. application as claimed in claim 2 is characterized in that, is applied to the preparation of the curative drug or the protective medicine of ischemia resisting heart and injury.
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| US20150246129A1 (en) * | 2012-12-26 | 2015-09-03 | Wockhardt Limited | Pharmaceutical composition |
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| CN1562357A (en) * | 2004-03-22 | 2005-01-12 | 中国人民解放军第四军医大学 | Medication use for external application of glucose-insulin-potassium polarization liquid for curing trauma and burn |
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| CN1562357A (en) * | 2004-03-22 | 2005-01-12 | 中国人民解放军第四军医大学 | Medication use for external application of glucose-insulin-potassium polarization liquid for curing trauma and burn |
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| 张锁龙等: "L-精氨酸对急性心肌梗死患者心功能和心律失常的影响", 《心脏杂志》 * |
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| US20150246129A1 (en) * | 2012-12-26 | 2015-09-03 | Wockhardt Limited | Pharmaceutical composition |
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Application publication date: 20111019 |