CN101474178A - Application of penehyclidine hydrochloride in preparing medicament for treating cardiogenic shock - Google Patents
Application of penehyclidine hydrochloride in preparing medicament for treating cardiogenic shock Download PDFInfo
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- CN101474178A CN101474178A CNA2009100581437A CN200910058143A CN101474178A CN 101474178 A CN101474178 A CN 101474178A CN A2009100581437 A CNA2009100581437 A CN A2009100581437A CN 200910058143 A CN200910058143 A CN 200910058143A CN 101474178 A CN101474178 A CN 101474178A
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- cardiogenic shock
- amyl ethyl
- ethyl quin
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Abstract
The invention relates to the use of penehyclidine hydrochloride in the preparation of medicines for treating cardiogenic shock diseases indicating that, in pathological changes, systolic pressure and mean arterial pressure decrease at least by 40%, the maximum rise speed of internal pressure of left ventricle (LV+dp/dtmax) decreases at least 80%, cardiac output decreases at least 40%. The application effect of the invention is shown by the influence of the penehyclidine hydrochloride on acute cardiogenic shock modles.
Description
Technical field
The invention belongs to medicine field, be specifically related to the application in preparation treatment cardiogenic shock medicine of the novel medical use of amyl ethyl quin ether hydrochloride, particularly amyl ethyl quin ether hydrochloride.The pathological change of described cardiogenic shock is presented as: systolic pressure and mean arterial pressure descend at least 40%, the maximum climbing speed (LV+dp/dt of left ventricular pressure
Max) descending at least 80%, cardiac output descends at least 40%.
Background technology
Amyl ethyl quin ether hydrochloride, English name Penehyclidine Hydrochloride, chemical name 3-(2-cyclopenta-2-hydroxyl-2-phenyl ethoxy) quinuclidine hydrochloride, molecular formula C
20H
29NO
2HCl, molecular weight 351.92.
Amyl ethyl quin ether hydrochloride is a kind of novel anticholinergic agent, has selectivity M
1, M
3And N
1, N
2Receptor antagonism all has very strong cholinolytic effect to maincenter and periphery, and to M
2Receptor does not have obvious effect, can effectively avoid atropine for want of tachycardia due to the m receptor subtype-selective and blocking-up presynaptic membrane M
2The receptor regulatory function, and drug effect is long and side effect is less, is mainly used in premedication and organophosphate poisoning at present and rescues.
Shock is the pathophysiological process of a complexity, it is the important vital organ hypoperfusion that is caused by multiple reason, blood supply oxygen supply obstacle, and then cause acidosis and dysbolismus, finally cause the function and the form damage of organ-tissue and cell, as untimely treatment, can bring out multiple organ dysfunction syndrome, cause shock to be difficult to reverse.
Shock can be divided into hypovolemic shock, septic shock, cardiogenic shock, neurogenic shock, anaphylactic shock by cause of disease classification; Be categorized as hyperdynamic shock (cardiac index is higher than normally, and total peripheral resistance is lower than normally) and hypodynamic (cardiac index is lower than normally, and total peripheral resistance is higher than normally) shock by hemodynamics; Be divided into slight shock, moderate shock, severe shock by light and heavy degree.
Cardiogenic shock: except the blood vessel inner capacities was not enough to, the relative or absolute minimizing of heart stroke can cause shock, and chief reason has following table 1:
The mechanism of table 1 cardiogenic shock and reason
The Therapeutic Principle of shock removes the reason that causes shock as early as possible, recovers effective circulating load as early as possible, corrects microcirculation disturbance, promotes cardiac function and recovers the human homergy.
The treatment shock mainly adopts blood transfusion, fluid infusion, rises blood pressure, infection and processing primary disease.
Preliminary treatment measure: give patient warming, lower limb are slightly raised to promote venous return, and hemostasis is checked air flue and ventilatory, and breathed to the artificial mechanical in case of necessity.Forbid from the oral cavity feed, as vomit that patient head need turn to a side in case suck.Because the low perfusion of tissue can not guarantee drug absorption, all medicines are as might giving from vein.Should avoid general anesthesia, but have the person of having an intense pain can quiet notes morphine 3-5mg/2min, duplicate injection after 15-20 minute in case of necessity.Though it is anxious that the low perfusion of brain can cause, should not be with tranquilizer or antianxiety drugs.
Supporting Therapy's measure: stablize the function (may need) of vital organ, give the face shield oxygen supply immediately with norepinephrine or dopamine.As suffer a shock serious or hypoventilation, then need put trachea tube with malleation high concentration O
2Assisted ventilation.
The patient that can not reverse rapidly shock all belongs to the critical patient, should (as ICU, CCU) continue treatment at special care unit.The project of careful monitoring comprises ECG; Arteriotony---preferably by direct intra-arterial intubate; Measure the breathing rate and the degree of depth; Urine amount (bladder indwelling catheter usually); Arterial blood Ph, PaO
2And PaCO
2Body temperature; And clinical setting, comprise consciousness, the pulse capacity, skin temperature and color and luster are surveyed CVP (central venous pressure), PCWP (pulmonary capillary wedge pressure PCWP pressure).To shock etiology unknown or the Combination cause of disease or serious shock, particularly has help with the pulmonary artery balloon catheter with thermodilution method thought-read output with the patient of serious oliguria or pulmonary edema.It is valuable to state of an illness detection to design good log, and it is also useful that series is measured arterial blood gas, Hct, serum creatinine and blood lactic acid.
The treatment of cardiogenic shock is to improve cardiac function, and shock should be inhaled O behind the acute myocardial infarction
2, the stable heart-rate and the rhythm of the heart are as normally then dilatation of PCWP.Shock often has sound response to quick dilatation after the RV myocardium infarction, obviously increase in inferior wall myocardial infarction right ventricle filling pressure (CVP) and do not have when tangible left ventricular filling pressure increases (pulmonary artery diastolic is pressed or PCWP latter stage) and should do above-mentioned consideration, but liquid make-up seldom can be corrected abnormal hemodynamics separately, adds the medicine that boosts possibly.Quiet pushing away can be alleviated serious chest pain in morphine 3-5mg2 minute, helped to lower the catecholamine levels that increases, and the preload and the afterload that lower failure heart; Because morphine can cause respiration inhibition, and be a kind of venectasia agent, can make blood pressure drops, so need its reaction of close observation after the medication: suppress or bad blood pressure response as apnea, but initial dose duplicate injection after 10 minutes.The quiet notes of atropine 1mg treatment severe bradycardia (heart rate＜50 time/minute=and the hypotension that takes place very early after symptom is initial is effective sometimes, especially at lower wall---rear wall myocardial infarction.Norepinephrine or dopamine are in order to keep systolic arterial pressure (but not〉110mmHg) more than 90mmHg.Isoproterenol obviously increases O
2Requirement, thereby be incompatible to shock behind the acute myocardial infarction, unless companion complete heart block person has the needs of temporary transient application.
When shock accompanies by bradycardia or height auriculoventricular block, rebuild blood pressure and correct acidosis with norepinephrine or dopamine Ventricular Rate is accelerated.There are persistence height auriculoventricular block or serious sinus node dysfunction may need patient, stop for a long time to fight or ventricular tachycardia or vibration accompany by serious bradycardia and often need the short time to use isoproterenol [2mg5% Glucose Liquid 500ml drips fast 1-4 μ g/min (0.25-1ml/min)] before pace-making repeatedly having through the vein temporary cardiac pacing.Not conventional use digoxin during shock but the supraventricular tachycardia patient is had value.Hypotension is not serious, and instillation dobutamine or amrinone (0.75mg/kg, 2-3 minute quiet pushing away are continued and instiled with per minute 5-10 μ g/kg) may be favourable to promoting heart stroke and lowering left ventricular filling pressure.When giving dobutamine tachycardia and arrhythmia may take place, especially when dosage is big.Because amrinone is positive inotropic medicament and vasodilation, when administration arrhythmia and hypotension can take place; Amrinone also can cause thrombocytopenia, so should monitor platelet count.Vasodilation (as sodium nitroprusside, nitroglycerin) increases the vein volume or reduces systemic vascular resistance, reduces the workload of damaged myocardium, so may be effectively to no severe hypotension person.Therapeutic alliance (being dopamine or dobutamine and sodium nitroprusside or nitroglycerin) may be effective especially to some patient, but need tight monitoring ECG and lung, body circulation hemodynamic index.
Early stage use intra aortic balloon counterpulsation maybe can be effective to the temporary reversible shock of acute myocardial infarction, need are kept blood pressure with the medicine that boosts (norepinephrine or dopamine)〉30 minutes patient and acute myocardial infarction merges perforation of ventricular septum or serious acute mitral incompetence person also should consider to adopt.The percutaneous puncture technical development makes balloon counterpulsation also can use in community hospital to inserting at bedside.
The emergency case surgery entangles to be controlled machinery damaged (as RIVS, pseudoaneurysm, serious mitral incompetence, the excision bulk does not have the myocardial segment of contractile function) and also needs.
As execution emergency case PTCA inaccessible arteria coronaria is led at acute myocardial infarction in initial a few hours again and can reverse cardiogenic shock.Before emergency case PTCA, whether use the intravenous injection thrombolytic drug still disputable, if but do not go to emergency case PTCA or operation on heart, as long as no anti-indication should adopt thromboembolism treatment as far as possible.
If the clinical medicine that is used for antishock drug main symptomatic treatment has untoward reaction more or less now, and is mainly as follows:
Morphine: the pain relieving that is mainly used in the patient who has an intense pain in shock takes place is used, and its mechanism of action is morphine exciting μ, κ and δ receptor, so produce the analgesic effect.Subcutaneous injection 5～10mg can obviously alleviate or eliminate pain, but consciousness and other feel unaffected.Morphine is all effective to various pain, and to the effectiveness of the chronic dull pain of persistence greater than the discontinuity sharp pain.Main adverse reactions is: logotype promptly produced drug resistance in 3～5 days, but 1 week above addiction, feel sick, vomiting, respiration inhibition, drowsiness, dizzy, constipation, dysuria, biliary colic etc.Anaphylaxiss such as accidental pruritus, urticaria, hydroderma, this product is mainly used in aspect the pain relieving in antishock clinical treatment.
Colloid solution: 6% hetastarch that is dissolved in 0.9%NaCl.Because in the treatment of hypovolemic shock, replenishing body fluid is to occupy consequence in the Therapeutic Principle, it is necessary adopting colloid solution to carry out the additional of body fluid.Hetastarch: after this product intravenous drip, the long period stays in the blood, improves plasma osmotic pressure, tissue fluid is refluxed increase, the blood volume that increases sharply, dilute blood, and increase the cell membrane negative charge, make aggregating cells depolymerization, reduce the whole body blood viscosity, microcirculation improvement.This product main adverse reactions is: infusion reaction can take place in idol.Urticaria, pruritus appear in small number of patients.This product is mainly used in the treatment of hypovolemic shock.
Sodium bicarbonate: vein gives 5% solution, is used for the treatment of metabolic acidosis.When shock takes place, the metabolic acidosis that mostly occurs, this product is mainly by acid-base reaction treatment metabolic acidosis.This product is mainly treatment metabolic acidosis medication in the shock.
Medicine norepinephrine or dopamine boost: the function of stablizing vital organ, correct abnormal hemodynamics, mainly improve the vital organ of appearance in shock takes place because the abnormal hemodynamics that blood pressure drops causes by the rising blood pressure, thereby has the function of stablizing vital organ, be the adrenoceptor excitomotor, be intensive α receptor agonism medicine, also exciting beta receptor of while.By the α receptor agonism, can cause that blood vessel extremely shrinks, make hypertension, coronary flow increases; By the excitement of beta receptor, myocardial contraction is strengthened, heart output increases.Main adverse reaction: medicine liquid leakage can cause local tissue necrosis, and intensive vasoconstriction can make the important organ organ blood flow reduce, and hypourocrinia after the kidney blood flow falls sharply organizes blood supply insufficiency to cause anoxia and acidosis; When using lastingly or in a large number, cardiac flow is reduced, peripheral vascular resistance raises, and cardiac output reduces, and consequence is serious; Along vein pathway skin whitening, injection site skin broke Collapse when the reaction that should pay attention to comprised venoclysis, and the skin cyanosis is rubescent, severe vertigo, though above-mentioned reaction belongs to rarely, consequence is serious; Individual patients has erythra, facial edema because of allergy; In anoxia, electrolyte balance imbalance, organic heart disease patient or during the amount of exceeding, arrhythmia can appear; The reflexive decreased heart rate can appear after the hypertension.
The vasodilation sodium nitroprusside: sodium nitroprusside can increase the vein volume or reduce systemic vascular resistance, reduces the workload of damaged myocardium, is a kind of vasodilator of quick-acting and part-time application.Tremulous pulse and vein smooth muscle all there is direct dilating effect.Vasodilation is lowered peripheral vascular resistance, thereby hypotensive effect is arranged.Vasodilation is all lowered the forward and backward load of heart, and cardiac output improves, so useful to heart failure.Afterload lowers the impedance of aorta and left ventricle when can reduce valvular insufficiency and alleviates and backflow.Main adverse reaction: blood pressure reduces too fast acute excessively, dizzy, profuse sweating, headache, muscle twitch, nervous or anxiety appear, agitation, stomachache, reflex tachycardia or arrhythmia, the generation of symptom is relevant with intravenously administrable speed, and is little with aggregate relation; Rhodanate is poisoned or during the amount of exceeding, and movement disorder, blurred vision, delirium, dizzy, headache, loss of consciousness can occur, feels sick, vomiting, tinnitus, breathe hard; When cyanide poisoning or excess, can occur that areflexia, stupor, hear sounds are remote, hypotension, asphygmia, skin powder redness, breathe shallow, platycoria.
Antibiotic: be mainly used in the treatment of septic shock, treat at the pathogenic bacterium that cause septic shock.Be divided into according to different situations: be used for the previous tretament under the not clear situation of pathogenic bacterium: gentamycin or tobramycin add the 3rd generation cephalosporin (cefotaxime or ceftriaxone are the then available ceftazidime of Rhodopseudomonas if suspect); May be due to the gram positive bacteria: then should add and use vancomycin; . the source of infection is at abdominal part: should use anti-anaerobic agent (as metronidazole).
Anticholinergic agent: atropine sulfate, pharmacokinetics is as follows: 15-20 minute blood drug level peak value after the intramuscular injection, oral is 1-2 hour, and effect is general to continue 4-6 hour, and the platycoria timeliness is longer.T
1/2Be 3.7-4.3 hour.Main hydrolysis metabolism by hepatocyte enzyme has 13-50% to discharge with urine with original shape in 12 hours approximately.The application of atropine sulfate in shock: by acting on the M cholinoceptor, thereby the spasm of removing smooth muscle (comprises releasing vasospasm, improve the blood capillary circulation), thereby improve the confusion of shock patients, sleepy common, hands and foot feel cold, moist, the normal cyanosis of skin and pale, the clinical sign that capillary filling time prolongs is through use for many years, the curative effect that atropine sulfate is used to suffer a shock is determined, but following untoward reaction: 0.5mg is also arranged, slight decreased heart rate, slightly xerostomia and hypohidrosis; 1mg, xerostomia, heart rate quicken, pupil slightly enlarges; 2mg, blurred vision appears in cardiopalmus, remarkable xerostomia, platycoria sometimes; 5mg, above-mentioned symptom increases the weight of, and has slurred speech, dysphoria, xerosis cutis heating, urine difficulty, enterokinesia to reduce; More than the 10mg, above-mentioned symptom is heavier, rapid pulse and a little less than, the central excitation phenomenon is serious, accelerated breathing is deepened, and delirium, hallucination, convulsions etc. occur; Can change inhibition over to by central excitation during serious the poisoning, produce stupor and respiratory paralysis etc.The minimum lethal dose (MLD) adult is about 80～130mg, and the child is 10mg.
Summary of the invention
The object of the present invention is to provide a kind of novel medical use, the particularly amyl ethyl quin ether hydrochloride application in preparation treatment cardiogenic shock medicine of amyl ethyl quin ether hydrochloride.
Cardiogenic shock of the present invention is meant that pathological change is presented as that systolic pressure and mean arterial pressure descend at least 40%, the maximum climbing speed (LV+dp/dt of left ventricular pressure
Max) descending 80% at least, cardiac output descends 40% at least.
Treatment cardiogenic shock medicine of the present invention can be liquid as injection, spray, aerosol, also can be solid, shaped such as tablet, capsule.
Liquid medium of the present invention is meant water, ethanol, freon or 134a.
Pharmaceutically acceptable adjuvant of the present invention is meant starch, Pulvis Talci, carboxymethyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl starch sodium, magnesium stearate or sucrose, and described capsule material is meant the husk that is prepared from by gelatin, G ﹠ W.
In the treatment cardiogenic shock medicine of the present invention, the mass percent concentration of amyl ethyl quin ether hydrochloride is 0.01%～2%.
Below by the amyl ethyl quin ether hydrochloride aqueous solution influence of dog acute cardiogenic shock model is proved that amyl ethyl quin ether hydrochloride is in the effect that is used for the treatment of aspect the cardiogenic shock.
Amyl ethyl quin ether hydrochloride is to the influence test of dog acute cardiogenic shock model
1.1 experiment material
1.1.1 experiment medicine
Amyl ethyl quin ether hydrochloride injection (long holder is peaceful): specification 1ml:1mg.Provided by Chengdu Lisite Pharmaceutical Co., Ltd., lot number is 060601.The clinical vein injection, first dose of 4mg, later per 6～8h or 6～12h keep to 2mg; Or first dose of 2mg, continuous 5 times, per hour 1 time.The medication cycle: 3～5 days.The clinical consumption of the adult of reference is 0.1667mg/kgd (10mg/60kgd) in this experiment, and the basic, normal, high dosage of dog is followed successively by 0.1667mg/kgd, 0.3334mg/kgd, 0.6668mg/kgd, 1,2,4 times of the clinical consumption that is equivalent to respectively to be grown up.Medicine is all with normal saline dilution preparation, the drug level that basic, normal, high dosage group and intramuscular injection (following all abbreviations " intramuscular injection ") high dose group animal is used is followed successively by 0.03334mg/ml, 0.06668mg/ml, 0.13336mg/ml, 0.13336mg/ml, and the administration volume is 5ml/kg.。
Positive control medicine: adrenalin hydrochloride injection (Adrenaline Hdrochloride Injection): Shanghai Hefeng Pharmaceutical Co., Ltd. produces, batch number: 5A09004, the accurate word H31021062 of traditional Chinese medicines; Specification: 1ml:1mg.The clinical consumption of the adult of reference is 0.01667mg/kgd (1mg/60kgd) in this experiment, and the dosage of dog is designed to 0.06668mg/kgd, 4 times of the clinical consumption that is equivalent to be grown up.Medicine is prepared with the normal saline dilution, and the drug concentrations of using is 0.01334mg/ml, and the administration volume is 5ml/kg.
1.1.2 laboratory animal and place
Healthy adult soil dog, 36, the male and female dual-purpose, female unpregnancy is about body weight 15kg, available from the countryside, Chengdu.By sex, body weight and operating time dog is divided into following 6 groups at random, every group of 6 animals are cooked 1～2 dog every day.Group has: dosage group and amyl ethyl quin ether high dose group in model control group, epinephrine group, amyl ethyl quin ether intramuscular injection group, amyl ethyl quin ether low dose group, the amyl ethyl quin ether.
Experiment place: Sichuan University's Experimental Animal Center, animal service condition (three grades) credit number: SYXK (river) 2004-46.
1.1.3 experimental apparatus
BIOPAC 16 road physiology monitors (USA BIOPAC Systems, Inc.) and accessory (as: TSD104A invasive blood pressure transducer); CBI-8,000 8 passage doppler flow inaging module plug-in casees (USA Crystal Biotech Inc.) and accessory thereof (as: Soft Doppler Flow Cuff (P/N E-20-[Φ=10mm, 8mm, 6mm, 4mm, 2mm, 1mm, 0.5mm etc.]), TRITON TECHNOLOGY, INC.); HX-300 animal respirator (Chengdu TME Technology Co., Ltd.); GD350-P type high frequency electric knife (Hutong Electronic Co., Ltd., Shanghai, the accurate card number of producing: No. the 3250087th, state's pencil tool (standard) word 2001; Other adnexa comprises: pole plate, cutter head, foot switch); The BP121S electronic balance (Made by Sartorius, Max120g, d=0.1mg, e=10d); Electronic thermometer (Shanghai medical apparatus factory); XTB-1 type anatomic microscope, LGY-150 type cold light source (south of the River photoelectricity group company instrument and meter factory); Operating lamp; XJ11D desk model sphygmomanometer (Shanghai Medical Equipment Factory) etc.
1.1.4 experiment reagent and equipment
Escherichia coli endotoxin main active lipopolysaccharide (LPS, Lipopolysaccharides from Escherichiacoli., 055:B5), by SIGMA-ALDRICH, Inc. produces, article No. is L2880-500MG, and lot number is 075K4038,2～8 ℃ of Store at;
(molecular formula is C to pentobarbital sodium for BR, Pentobarbital sodium
11H
17N
2NaO
3, molecular weight (FW) is 248.26, Chinese Chemical Reagent Co., Ltd., Sinopharm Group, lot number (Lot. № .): WS20050411), be mixed with 3% solution with physiological saline solution;
(Heprinar, molecular weight are about 6000～20000 to heparin sodium, the Long Huagongshijichang of Chengdu section, lot number: 050308), be mixed with 0.5% solution with physiological saline solution;
Sodium chloride injection (0.9%, Sodium chloride injection, Kelun Pharm Ind Co., Ltd., Sichuan, lot number: B 05 09 30-R);
Dextrose and Sodium Chloride Inj. (Kelun Pharm Ind Co., Ltd., Sichuan, lot number: H050611 F).
(prescription is Tyrode ' s solution: NaCL 8g/L, KCL 0.2g/L, MgCL
20.1g/L, NaH
2PO
42H
2O 0.05g/L, NaHCO
31.0g/L, CaCL
2(0.2g/L the back adds), Glucose 1.0g/L (facing the time spent adding),
Below Experimental formula herewith), sodium chloride (chemistry chemical reagent work of burnt alkali group, lot number is 20000706), potassium chloride (Chengdu chemical reagent factory, lot number is 990928), magnesium chloride (Mg CL
2The Long Huagongshijichang of Chengdu section, lot number 20040902), sodium dihydrogen phosphate (Kingsoft, Chengdu chemical reagent factory, lot number 20001011), sodium bicarbonate (is gone up marine rainbow photoinitiator chemical factory, lot number 010421), calcium chloride (chemical plant among Deng of Tianjin City Tanggu, lot number 20000106), glucose (Sichuan Fei Deli pharmaceutical Co. Ltd, lot number 040901).
Department of pediatrics is some with machine for chest-opening, heart scissors, blood capillary mosquito forceps, mosquito forceps, needle holder, dressing forceps, operating scissors, eye scissors, ophthalmology tweezer, scalpel etc.; The operation needlework are some;
Plastic three-way valve (the sharp medical apparatus and instruments company limited of Sino-U.S. cooperation Wenzhou China); Syringe (1ml, 2.5ml, 5ml, 10ml type); Transfusion device (intravenous anesthesia is used); Medical absorbent cotton; Medical cotton stick; The hospital gauze piece; Disposable rubber gloves; Hawser.
Own product: dog head folder; Tracheal intubation (or Y type glass intubate); Femoral venous catheter; The carotid artery intubate; The ventricle intubate; The water manometer.
1.2 experimental technique
1. the preceding fasting of dog experiment is 12 hours, weighs, with the intravenous anesthesia of pentobarbital sodium (pressing 30mg/kg) back leg.
2. left femoral vein intubate, persistent instillation 5% glucose solution.
3. tracheal intubation connects artificial respirator (EXP/INSP=5:4, Respiratory Frequency=18～20/min, Tidal Volume ≈ 150～200ml).
4. separate right carotid, place Doppler flowmeter probe (diameter is each one of 3mm, 4mm), measure and record cerebral blood flow and blood flow rate.
Separate left carotid again, the insertion ductus arteriosus connects pressure transducer (noting with the desk model sphygmomanometer calibration, down together), measures also record periphery blood pressure.
5. second and third intercostal or third and fourth intercostal thoracotomy on the left of, machine for chest-opening is broadened one's vision, and exposes heart, cuts off pericardium, makees the pericardium cradle.
Separate aortic root, place Doppler flowmeter probe (suitably diameter), measure and record cardiac output and blood flow rate.
Left ventricle tip intubate connects pressure transducer, measures and the record left indoor pressure.
6. left femoral vein is injected after heparin solution (125U/kg) stablizes 10 minutes, constant speed is imported 2% pentobarbital sodium (0.2ml/kg/min) herein, intrinsic pressure and cardiac output decline 40% index as cardiogenic shock with carotid artery, after this speed with 0.08ml/kg/min keeps 10min.
7. write down basic value after the modeling: comprise indexs such as Blood pressure of carotid artery, left ventricular pressure, cardiac output, cerebral blood flow.
8. more immediately sublingual vein give relative medicine, model control group gives normal saline.
9. write down 5min, 10min after the administration, 20min, 30min, each desired value of 40min, 60min.
1.3 observation index
1.3.1 myocardiac mechanics index
After by BIOPAC 16 road physiology monitor bio signal analytical systems Blood pressure of carotid artery figure and left ventricular pressure figure being carried out analyzing and processing, can get the value of following index: heart rate (HR), systolic pressure (SP/SBP), diastolic pressure (DP/DBP), mean arterial pressure (MAP), left ventricle systole peak pressure (LVSP, LVP
Max), left ventricular diastolic end presses (LVEDP), the maximum rate of change (LV ± dp/dt of left ventricular pressure
Max, or dp/dt
Max, dp/dt
Min), left chamber begins to be contracted to left indoor pressure climbing speed time to peak (t-dp/dt
Max, i.e. t (LVEDP) → t (dp/dt
Max)), Vce-cpip is (during the most high appearance systolic pressure
The shortening speed [Vce] of cardiac muscle fiber contractile element), wherein LVEDP, t-dp/dt
Max, after three of Vce-cpiD etc. all read five values, average again.
Statistical procedures: use SPSS 10.0 for windows softwares and carry out statistical procedures, all data are with " mean ± standard deviation (x ± s) " expression.The relatively employing one factor analysis of variance of many group sample averages: at first each group data is carried out the normal state check, adopt one factor analysis of variance (ONE-WAY ANOVA) when meeting normal distribution, adopt non parametric tests (Nonparametric Tests) when not meeting.The concrete steps of every observation index and derivation parameter being carried out statistical procedures are, measured value with different observing times carries out administration front and back self relatively (within group variance analysis or non parametric tests), its percentage rate (certain time point refers to target value/normal value or basic value after the=administration, down together) carries out the between group variable analysis or its significance is relatively judged in non parametric tests." * " (P＜0.05) is for difference has significant statistical significance, and there is the statistical significance of highly significant " * * " (P＜0.01) for difference.
1.3.2 hemodynamic index
Measure cardiac output (CO) and cerebral blood flow.
Statistical procedures: with the statistical procedures under " 1.3.1 myocardiac mechanics index " item.
1.4 experimental result
1.4.1 myocardiac mechanics index
1.4.1.1 heart rate (HR)
The result sees table 2 for details.
With basic value after the modeling relatively, the heart rate of model control group does not have significant change (p〉0.05); The heart rate of epinephrine group is obviously accelerated (p＜0.05) when 5min, 10min, three time points of 60min.
With model control group relatively, the heart rate percentage rate of epinephrine group is obviously accelerated (p＜0.05) when 15min, and the effect of amyl ethyl quin ether all not obvious (p〉0.05).
1.4.1.2 systolic pressure (SP/SBP)
The result sees table 3 for details.
With basic value after the modeling relatively, the systolic pressure of model control group does not have significant change (p〉0.05); The systolic pressure of epinephrine group is all obviously risings (p＜0.05) when 10min, 20min, three time points of 40min.
With model control group relatively, the systolic pressure percentage rate of epinephrine group all obviously raises (p＜0.05) when six time points, and the effect of amyl ethyl quin ether all not obvious (p〉0.05).
1.4.1.3 diastolic pressure (DP/DBP)
The result sees table 4 for details.
With basic value after the modeling relatively, the diastolic pressure of model control group does not have significant change (p〉0.05); The diastolic pressure of the diastolic pressure of amyl ethyl quin ether low dose group dosage group when 60min, in the amyl ethyl quin ether obviously reduces (p＜0.05 or p＜0.01) when two time points of 40min, 60min.
Compare with model control group, the diastolic pressure percentage rate of epinephrine group all obviously raises (p＜0.05 or p＜0.01) when 5min, 10min, 20min, 40min, five time points of 60min, and the diastolic pressure percentage rate of dosage group obviously reduces (p＜0.01) in the amyl ethyl quin ether when 40min.
1.4.1.4 mean arterial pressure (MAP)
The result sees table 5 for details.
With basic value after the modeling relatively, the mean arterial pressure of model control group does not have significant change (p〉0.05); The mean arterial pressure of epinephrine group is all obviously risings (p＜0.05 or p＜0.01) when 5min, 10min, 20min, 30min, five time points of 40min.
Compare with model control group, the mean arterial pressure percentage rate of epinephrine group is all obviously risings (p＜0.01) when 5min, 10min, 20min, 30min, six time points of 40min, 60min; And the effect of amyl ethyl quin ether all not obvious (p〉0.05).
1.4.1.5 left ventricle systole peak pressure (LVSP, LVP
Max)
The result sees table 6 for details.
Compare with basic value after the modeling, the left ventricle systole peak pressure of model control group obviously reduces (p＜0.05) when 5min, but the left ventricle systole peak pressure of epinephrine group all obviously raises when 5min, 10min, four time points of 20min, 40min (p＜0.05).
Compare with model control group, the left ventricle systole peak pressure percentage rate of epinephrine group is all obviously risings (p＜0.05 or p＜0.01) when 5min, 10min, 20min, 30min, five time points of 40min; And the effect of amyl ethyl quin ether all not obvious (p〉0.05).
1.4.1.6 the maximum climbing speed (LV+dp/dt of left ventricular pressure
Max)
The result sees table 7 for details.
With basic value after the modeling relatively, the maximum climbing speed of left ventricular pressure of each group does not all have significant change (p〉0.05).
With model control group relatively, the maximum climbing speed percentage rate of left ventricular pressure of each group of each time point does not all have significant change (p〉0.05).
1.4.1.7 left chamber begins to be contracted to left indoor pressure climbing speed time to peak (t-dp/dt
Max)
The result sees table 8 for details.
Compare the t-dp/dt of each group with basic value after the modeling
MaxAll there is not significant change (p〉0.05).
Compare t-dp/dt of each group of each time point with model control group
MaxPercentage rate does not all have significant change (p〉0.05).
1.4.1.8 the shortening speed (Vce-cpip) of the cardiac muscle fiber contractile element during the most high appearance systolic pressure
The result sees table 9 for details.
With basic value after the modeling relatively, Vce-cpip of each group does not all have significant change (p〉0.05).
With model control group relatively, the Vce-cpip percentage rate of amyl ethyl quin ether intramuscular injection group when 5min, 20min, three time points of 30min, obviously raise (p＜0.05).
1.4.1.9 (LVEDP) pressed at the left ventricular diastolic end
The result sees table 10 for details.
With basic value after the modeling relatively, LVEDP of each group does not all have significant change (p〉0.05).
With model control group relatively, the LVEDP percentage rate of amyl ethyl quin ether intramuscular injection group when 30min, obviously raise (p＜0.05).
1.4.1.10 the maximum fall off rate (LV-dp/dt of left ventricular pressure
Max)
The result sees table 11 for details.
Compare the LV-dp/dt of each group with basic value after the modeling
MaxAll there is not significant change (p〉0.05).
Compare LV-dp/dt of each group of each time point with model control group
MaxPercentage rate does not all have significant change (p〉0.05).
1.4.2 hemodynamic index
1.4.2.1 cardiac output (CO)
The result sees table 12 for details.
With basic value after the modeling relatively, the cardiac output of model control group does not have significant change (p〉0.05), but the cardiac output of epinephrine group all obviously raises when 5min, 10min, 20min, 30min, five time points of 40min (p＜0.05).
Compare with model control group, the cardiac output percentage rate of epinephrine group is all obviously risings (p＜0.05 or p＜0.01) when 5min, 10min, 20min, 30min, six time points of 40min, 60min; And the effect of amyl ethyl quin ether all not obvious (p〉0.05).
1.4.2.2 cerebral blood flow
The result sees table 13 for details.
With basic value after the modeling relatively, the cerebral blood flow of dosage group when two time points of 5min, 10min, obviously raise (p＜0.05) in the amyl ethyl quin ether.
With model control group relatively, the cerebral blood flow percentage rate of dosage group when two time points of 5min, 10min, obviously raise (p＜0.05) in the amyl ethyl quin ether.
Table 2 amyl ethyl quin ether hydrochloride to the influence of dog acute cardiogenic shock model center rate (HR) (x ± s, n=6)
(continuous table 2)
Annotate: organize interior comparison with basic value after the modeling, #p＜0.05, ##p＜0.01; And model control group compares between organizing, * p＜0.05, * * p＜0.01.
Table 3 amyl ethyl quin ether hydrochloride to the influence of systolic pressure (SP/SBP) in the dog acute cardiogenic shock model (x ± s, n=6)
(continuous table 3)
Annotate: organize interior comparison with basic value after the modeling, #p＜0.05, ##p＜0.01; And model control group compares between organizing, * p＜0.05, * * p＜0.01.
Table 4 amyl ethyl quin ether hydrochloride to the influence of diastolic pressure (DP/DBP) in the dog acute cardiogenic shock model (x ± s, n=6)
(continuous table 4)
Annotate: organize interior comparison with basic value after the modeling, #p＜0.05, ##p＜0.01; And model control group compares between organizing, * p＜0.05, * * p＜0.01.
Table 5 amyl ethyl quin ether hydrochloride to the influence of mean arterial pressure (MAP) in the dog acute cardiogenic shock model (x ± s, n=6)
(continuous table 5)
Annotate: organize interior comparison with basic value after the modeling, #p＜0.05, ##p＜0.01; And model control group compares between organizing, * p＜0.05, * * p＜0.01.
Table 6 amyl ethyl quin ether hydrochloride is to left ventricle systole peak pressure (LVSP, LVP in the dog acute cardiogenic shock model
Max) influence (x ± s, n=6)
(continuous table 6)
Annotate: organize interior comparison with basic value after the modeling, #p＜0.05, ##p＜0.01; And model control group compares between organizing, * p＜0.05, * * p＜0.01.
Table 7 amyl ethyl quin ether hydrochloride is to the maximum climbing speed (LV+dp/dt of left ventricular pressure in the dog acute cardiogenic shock model
Max) influence (x ± s, n=6)
(continuous table 7)
Annotate: organize interior comparison with basic value after the modeling, #p＜0.05, ##p＜0.01; And model control group compares between organizing, * p＜0.05, * * p＜0.01.
Table 8 amyl ethyl quin ether hydrochloride is to t-dp/dt in the dog acute cardiogenic shock model
MaxThe influence of (left chamber begins to be contracted to left indoor pressure climbing speed time to peak) (x ± s, n=6)
(continuous table 8)
Annotate: organize interior comparison with basic value after the modeling, #p＜0.05, ##p＜0.01; And model control group compares between organizing, * p＜0.05, * * p＜0.01.
Table 9 amyl ethyl quin ether hydrochloride to the influence of Vce-cpip in dog acute cardiogenic shock model when appearance systolic pressure (the most high Vce) (x ± s, n=6)
(continuous table 9)
Annotate: organize interior comparison with basic value after the modeling, #p＜0.05, ##p＜0.01; And model control group compares between organizing, * p＜0.05, * * p＜0.01.
Table 10 amyl ethyl quin ether hydrochloride to left ventricular diastolic end in the dog acute cardiogenic shock model press (LVEDP) influence (x ± s, n=6)
(continuous table 10)
Annotate: organize interior comparison with basic value after the modeling, #p＜0.05, ##p＜0.01; And model control group compares between organizing, * p＜0.05, * * p＜0.01.
Table 11 amyl ethyl quin ether hydrochloride is to the maximum fall off rate (LV-dp/dt of left ventricular pressure in the dog acute cardiogenic shock model
Max) influence (x ± s, n=6)
(continuous table 11)
Annotate: organize interior comparison with basic value after the modeling, #p＜0.05, ##p＜0.01; And model control group compares between organizing, * p＜0.05, * * p＜0.01.
Table 12 amyl ethyl quin ether hydrochloride to the influence of dog acute cardiogenic shock model center output (CO) (x ± s, n=6)
(continuous table 12)
Annotate: organize interior comparison with basic value after the modeling, #p＜0.05, ##p＜0.01; And model control group compares between organizing, * p＜0.05, * * p＜0.01.
Table 13 amyl ethyl quin ether hydrochloride to the influence of cerebral blood flow in the dog acute cardiogenic shock model (x ± s, n=6)
(continuous table 13)
Annotate: organize interior comparison with basic value after the modeling, #p＜0.05, ##p＜0.01; And model control group compares between organizing, * p＜0.05, * * p＜0.01.
1.5 brief summary
Constant speed is imported 2% pentobarbital sodium, can make dog the pathological change of cardiogenic shock occur, descends (40%) the maximum climbing speed (LV+dp/dt of left ventricular pressure at least as systolic pressure and mean arterial pressure
Max) descend (about 80%) cardiac output descend at least (about 40%) at least.So make dog acute cardiogenic shock model, observe the therapeutical effect of epinephrine, amyl ethyl quin ether on this basis.
The result shows: epinephrine can obviously be accelerated heart rate, and rising systolic pressure, mean arterial pressure and left ventricle systole peak pressure increase cardiac output, so the acute cardiogenic shock dog is had the obvious treatment effect.
The amyl ethyl quin ether hydrochloride intravenously administrable can obviously reduce diastolic pressure, cerebral blood flow increasing amount, and mean arterial pressure and cardiac output are had the improvement effect, so the amyl ethyl quin ether hydrochloride intravenously administrable has therapeutical effect to the acute cardiogenic shock dog.
Below by the specific embodiment foregoing of the present invention is described in further detail again, but this should be interpreted as technical solution of the present invention only limits to following examples.
The specific embodiment
Embodiment 1
Amyl ethyl quin ether hydrochloride 0.1g
Water 1000ml
Be prepared as 50 bottles of 1000 of treatment cardiogenic shock medicine amyl ethyl quin ether hydrochloride injection or sprays.
Embodiment 2
Amyl ethyl quin ether hydrochloride 1g
Water 1000ml
Be prepared as 50 bottles of 1000 of treatment cardiogenic shock medicine amyl ethyl quin ether hydrochloride injection or sprays.
Embodiment 3
Amyl ethyl quin ether hydrochloride 5g
Water 1000ml
Be prepared as 50 bottles of 1000 of treatment cardiogenic shock medicine amyl ethyl quin ether hydrochloride injection or sprays.
Embodiment 4
Amyl ethyl quin ether hydrochloride 0.1g
Ethanol 10ml
Propellant 134a 1000g
Be prepared as 50 bottles of treatment cardiogenic shock medicine amyl ethyl quin ether hydrochloride aerosols.
Embodiment 5
Amyl ethyl quin ether hydrochloride 1g
Ethanol 10ml
Propellant 134a 1000g
Be prepared as 50 bottles of treatment cardiogenic shock medicine amyl ethyl quin ether hydrochloride aerosols.
Embodiment 6
Amyl ethyl quin ether hydrochloride 5g
Ethanol 10ml
Propellant 134a 1000g
Be prepared as 50 bottles of treatment cardiogenic shock medicine amyl ethyl quin ether hydrochloride aerosols.
Embodiment 7
Amyl ethyl quin ether hydrochloride 0.1g
Carboxymethyl cellulose 500g
Magnesium stearate 2g
Pulvis Talci 4g
Starch slurry is an amount of
Be prepared as 1000 of 1000 in treatment cardiogenic shock medicine amyl ethyl quin ether hydrochloride tablet or capsules.
Embodiment 8
Amyl ethyl quin ether hydrochloride 1g
Carboxymethyl cellulose 500g
Magnesium stearate 2g
Pulvis Talci 4g
Starch slurry is an amount of
Be prepared as 1000 of 1000 in treatment cardiogenic shock medicine amyl ethyl quin ether hydrochloride tablet or capsules.
Embodiment 9
Amyl ethyl quin ether hydrochloride 5g
Carboxymethyl cellulose 500g
Magnesium stearate 2g
Pulvis Talci 4g
Starch slurry is an amount of
Be prepared as 1000 of 1000 in treatment cardiogenic shock medicine amyl ethyl quin ether hydrochloride tablet or capsules.
Claims (6)
1, the application of amyl ethyl quin ether hydrochloride in preparation treatment cardiogenic shock medicine.
2, cardiogenic shock as claimed in claim 1 is meant that pathological change is presented as that systolic pressure and mean arterial pressure descend at least 40%, and the maximum climbing speed of left ventricular pressure descends at least 80%, and cardiac output descends at least 40%.
3, a kind of treatment cardiogenic shock medicine as claimed in claim 1 is liquid or solid, shaped.
4, a kind of liquid treatment cardiogenic shock medicine as claimed in claim 3, it is to be dissolved in liquid medium or to be suspended in the liquid medium and to get with amyl ethyl quin ether hydrochloride, described liquid medium is water, ethanol, freon or 134a.
5, a kind of solid, shaped treatment cardiogenic shock medicine as claimed in claim 3, it is by amyl ethyl quin ether hydrochloride and the pharmaceutically direct compression moulding of acceptable adjuvant mix homogeneously, or by amyl ethyl quin ether hydrochloride with pharmaceutically form with capsule material parcel behind the acceptable adjuvant mix homogeneously; Described pharmaceutically acceptable adjuvant is meant starch, Pulvis Talci, carboxymethyl cellulose, hydroxypropyl emthylcellulose, carboxymethyl starch sodium, magnesium stearate or sucrose; Described capsule material is meant the husk that is prepared from by gelatin, G ﹠ W.
6, a kind of as claim 1,3,4 or 5 described treatment cardiogenic shock medicines, wherein the content of amyl ethyl quin ether hydrochloride is 0.01%～2%.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102525909A (en) * | 2012-02-29 | 2012-07-04 | 黄绍渊 | Method for preparing penehyclidine hydrochloride injection |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102525909A (en) * | 2012-02-29 | 2012-07-04 | 黄绍渊 | Method for preparing penehyclidine hydrochloride injection |
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