CN103638023A - Application of penehyclidine hydrochloride in treatment of microcirculation disturbance caused by toxic shock infection after comprehensive treatment measures such as supplementing blood volume and the like - Google Patents
Application of penehyclidine hydrochloride in treatment of microcirculation disturbance caused by toxic shock infection after comprehensive treatment measures such as supplementing blood volume and the like Download PDFInfo
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- CN103638023A CN103638023A CN201310707433.6A CN201310707433A CN103638023A CN 103638023 A CN103638023 A CN 103638023A CN 201310707433 A CN201310707433 A CN 201310707433A CN 103638023 A CN103638023 A CN 103638023A
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Abstract
The invention discloses application of penehyclidine hydrochloride in treatment of microcirculation disturbance caused by toxic shock infection after comprehensive treatment measures such as supplementing blood volume and the like. The toxic shock infection disclosed by the invention is the shock caused by bacteria attack. The effect of the penehyclidine hydrochloride is proved by the effect on microcirculation disturbance caused by toxic shock infection of rabbits by a penehyclidine hydrochloride water solution.
Description
Technical field
The invention belongs to medicine field, be specifically related to the novel medical use of amyl ethyl quin ether hydrochloride, still there is the application of the situation of microcirculation disturbance in treatment infection toxic shock in amyl ethyl quin ether hydrochloride particularly through comprehensive treatment measures such as replenishment of blood content, described infection toxic shock refers to the shock being caused by germ attack.
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 is without obvious effect, can effectively avoid for want of tachycardia and blocking-up presynaptic membrane M due to m receptor subtype-selective of atropine
2regulation function, and drug effect is long and side effect is less, is mainly used at present premedication and organophosphate poisoning and rescues.
Shock is a kind of extremely critical and dangerous clinical disease, and onset is anxious, and PD is rapid, as rescued not in time and treating, can jeopardize patient's life at any time.
The essence of shock is that body is subject to the various factors of seriously curing the disease (infection, wound, Hypovolemia, allergy, poisoning, heart or neuromuscular illness etc.), the acute effective blood volume causing reduces, cardiac output declines, vasomotor dysfunction, directly or indirectly causes the minimizing of histoorgan hemoperfusion, anaerobic metabolism to increase and handicapped clinical syndrome.
The common classification of suffering a shock has:
(1) hypovolemic shock: refer to that blood effective ingredient loses, comprise hemorrhagic shock, the slurry property of losing blood shock and indecorous fluidity shock.
(2) traumatic shock: except with lose blood, lose outside the Pass Efficient Cycle amount that liquid etc. causes reduces and have, after tissue injury, the detoxifying function of catabolite and strong pain stimulation are also important factors.
(3) infect toxic shock: the pathogen of infection focus and toxin by blood absorption after due to shock.
(4) neurogenic shock: the neural reflex vasodilation that intense stimulus causes, the shock due to effective blood volume declines.
(5) cardiogenic shock: heart stroke decline blood pressure drops and microcirculation disturbance that cardiac dysfunction causes.
(6) anaphylactic shock: the shock that body causes allergy such as some drugs, food, serum.
The basic pathological change of shock is that tissue perfusion is not enough, and its key is again microcirculation disturbance.
Microcirculation disturbance is an important step in shock morbidity link, and cell injury can not be utilized oxygen and nutrient substance, and causing energy decline is the essence of shock.
If the clinical medicine for antishock drug main symptomatic treatment, has untoward reaction more or less now, mainly as follows:
1, supplement effective blood volume
Crystalloid fluid: Ringer lactate solution, compound NaCl, 5%-10% glucose saline etc. are containing the solution of sodium.The supplementary organismic internal environment that can recover of crystalloid fluid is stablized, and appropriate input can also improve and safeguard the filtration rate of renal tubular function and glomerule containing sodium solution.
Colloidal solution: low molecular dextran, albumin, blood plasma, whole blood.Wherein, after hetastarch intravenous drip, the long period stays in blood, improve plasma osmotic pressure, tissue fluid is refluxed and increase, blood volume increases sharply, dilute blood, and increase cell membrane negative charge, and make the cell depolymerization assembled, reduce whole body blood viscosity, improve microcirculation, be mainly used in the treatment of hypovolemic shock, its main untoward reaction is: occasionally infusion reaction can occur, urticaria, pruritus appear in small number of patients.Dextran can reduce viscosity of blood, prevent thrombosis, reduce disseminated inravascular coagulation generation and improve microcirculation, also have an osmotic diuresis effect, prevent renal failure, its untoward reaction is: in medication process, anaphylaxis may occur, as there is anaphylaxis drug withdrawal in time, use the excessive clotting mechanism that disturbs, increase the weight of heart of patient burden, forbid in hemorrhage or thrombocytopenia.Whole blood and blood plasma can maintain effective blood volume, improve anemia and histanoxia, avoid and improve organ dysfunction, but blood transfusion process should be prudent.
2, correct acidosis: acidosis can increase the weight of microcirculation dysfunction, is unfavorable for the recovery of blood volume, must note correcting acidosis, often mends 5% sodium bicarbonate.
3, vasoactive agent: patients with septic shock is to use the absolute indication of vasoactive drug, expands blood vessel pressor agent, contributes to improve microcirculation, protection organ function.
Conventional vasoactive agent has:
(1) vasoconstrictor: norepinephrine, vasopressin
(2) vasodilation
Dopamine hydrochloride: be α, beta receptor agonist, make visceral vessel expansion, renal blood flow increase, myocardial contraction strengthens, and untoward reaction is: during heavy dose of use, can occur breathing acceleration, arrhythmia.
Phentolamine: pharmacological action blocking-up alpha-receptor, improve microcirculation and reduce the drag loading of heart, untoward reaction is: can have orthostatic hypotension, nasal obstruction, feel sick, vomiting, serious arteriosclerosis, heart organic lesion etc., renal hypofunction person avoids use.
(3) nitrate esters expands blood vessel medicine: nitroglycerin and sodium nitroprusside, sodium nitroprusside is to work by discharging NO in body, resistance vessel and capacitance vessel are had to equal relexation, it can reduce Peripheral resistance, and lightening heart load increases effectively perfusion of tissue, thereby improve microcirculation, untoward reaction is: instil too fast, be prone to acute blood pressure drops, be prone to nauseating, vomiting, spirit uneasiness, muscle spasm etc. in medication process.This medicine needs now with the current, and keep in Dark Place, and should avoid and other drug 5 use, anemia of pregnant woman's forbidding, renal insufficiency and hypothyroidism person are cautious use of.
At present clinically for the treatment guide that infects toxic shock, comprise the use, infection, oxygen therapy (comprising mechanical ventilation) of liquid resuscitation, vasoactive agent, strictly control the comprehensive treatment measures such as hyperglycemia, blood transfusion, blood purification.In following experiment, selected conventional clinically treatment scheme and first-line drug, wherein, comprehensive treatment measure 1 is oxygen uptake+compound NaCl+dopamine hydrochloride, and comprehensive treatment measure 2 is penicillin sodium+compound NaCl+dopamine hydrochloride.
Summary of the invention
The object of the present invention is to provide amyl ethyl quin ether hydrochloride to infect toxic shock in treatment and through comprehensive treatment measures such as replenishment of blood content, still have the application of the situation of microcirculation disturbance.
Infection toxic shock of the present invention refers to the shock being caused by germ attack.
Described effect of the present invention is by amyl ethyl quin ether hydrochloride, rabbit to be infected to the impact of microcirculation disturbance due to toxic shock to prove.
The specific embodiment
Amyl ethyl quin ether hydrochloride infects toxic shock in treatment and through comprehensive treatment measures such as replenishment of blood content, still has the application test of the situation of microcirculation disturbance.
experiment material
1.1.1 Experimental agents
Penehyclidine hydrochloride injection (long holder is peaceful): anticholinergic agent, shock treatment.Specification: 1ml:1mg.By Chengdu Lisite Pharmaceutical Co., Ltd., provided, lot number is 111201.Clinical vein injection, first dose of 6mg, optionally every 12h gives 2mg and maintains later, and accumulated dose is 10mg/d.
Adult's quantity of reference in this experiment is 0.1667 mg/kgd(10 mg/60kgd), by man and animal dosage reduction formula A=kW
2/3/ 10000 calculate, and the dosage of rabbit is 0.3632 mg/kgd, and medicine is prepared with normal saline dilution, and concentration is 0.018162 mg/ ml, and administration volume is 10ml/kg.
Pentobarbital sodium (Pentobarbital sodium salt), specification 5g, is produced lot number: 6900183 by Solarbio company.
Compound sodium chloride injection (Compound Sodium Chloride Injection), interior sodium chloride-containing 0.85% ﹑ potassium chloride 0.03% ﹑ calcium chloride 0.033%.By Cologne, Sichuan, pharmaceutcal corporation, Ltd produces, authentication code: the accurate word H20043818 of traditional Chinese medicines, lot number is M13070725.
Dopamine hydrochloride inj (Dopamine Hydrochloride Injection), specification 2ml:20mg, by Jiangsu, pharmaceutcal corporation, Ltd of Ya Bang Johnson & Johnson produces, authentication code: the accurate word H32023366 of traditional Chinese medicines, lot number is 120411.
Benzylpenicillin sodium for injection (Benzylpenicillin Sodium for Injection), specification 2.4g (400Wan unit), is produced by HARBIN PHARMACEUTICAL GROUP CO., LTD. General Pharm. Factory, authentication code: the accurate word H23020930 of traditional Chinese medicines, lot number is A130101017.
laboratory animal and place
50 of Japan large ear rabbits, body weight 2.4-2.8kg, is divided into 5 groups (n=10) at random, and male and female half and half are provided animal production licence number by Sichuan Province plant of laboratory animal special commission: SCXK(river) 2008-14.Rabbit full-valence pellet feed, is provided by Sichuan Province plant of laboratory animal special commission.Freely drink urban life drinking-water.Feeding environment is conventional system, 16～26 ℃ of temperature, relative humidity 40～70%, gravity-flow ventilation, ventilation, natural lighting.
Experimental site: Chengdu qi xanthate thing non-clinical study company limited, animal occupancy permit number: SYXK(river) 2010-096.
experiment reagent and equipment
A type Neisseria meningitidis (NM, Lot:NM-A 1987), is provided by Southwest University for Nationalities Preventive Veterinary Medicine laboratory.Strain culturing, in 100ml meat soup, is cultivated 18h for 36 ℃, is then inoculated in Sanguis caprae seu ovis agar-agar dull and stereotyped, and 36 ℃, at 5%CO
2lower cultivation 18h, collects thalline, with normal saline, washes 2 times.Turbidimetry records thalline quantity (bacterium liquid ultimate density 1x10
11cFU/ml), bacterium liquid is stored in-20 ℃.
BP221S type electronic balance (SARTORIUS), JY601 type electronic balance (the above flat instrument and meter of current chart company limited), syringe is some, venous incubation device, the micro-infusion pump in ep2709-2 (German fresenius-kabi company), the colored plug-in type monitor (medical apparatus corporation, Ltd of U.S. Hewlett-Packard) of HEWLETT M1166A64S, the colored micro-circulation scanning tunnelling microscope (Xuzhou medical apparatus and instruments factory product) of WX-84 type constant temperature, Inspira ASVP animal respirator (Harvard Apparatus), BI-2000 medical image analysis system (Sichuan Tai Meng electronics corporation product), TonocapTM monitor (modelTC-200, Tonom etrics, Datex-Ohm eda Division).
experimental technique
After family's rabbit ear vein injection pentobarbital sodium anesthesia (30mg/kg), lie on the back fixing (as there is the situation of reviving, appending former dosage 20～40%).Row abdomen median line otch 1～2cm, gets one section of mesostenium and is placed on the lucite convex observation platform that is full of the lucite constant temperature water bath of 38 ℃ of Tyrode liquid and is laid in bath central authorities, presses fixing head.Utilize on the colored micro-circulation scanning tunnelling microscope of WX-84 type constant temperature video image under SONY camera collection microscope, by video frequency collection card, input microcomputer, utilize BI-2000 medical image analysis system to carry out real-time analysis to video image under gathered mirror.Fix a visual field, the indexs such as the arteriole caliber of observation selection area, arteriole flow velocity, point of intersect of the capillary network counting.In stomach undercut, insert carbon dioxide monitoring conduit (Tonom etrics
tM, Datex-Ohm eda D iv ision, Instrum entarium Corp), close subsequently abdominal cavity, record CO
2tension force.
Expose rabbit right flank butt crack, free right common femoral artery, ligation far-end, near-end inserts polyethylene catheter, connects tremulous pulse pressure tester, continues to monitor mean arterial pressure.Free right lateral thigh vein, inserts polyethylene catheter.
Animal is divided into 5 groups at random, and group is: A group (blank), B group (comprehensive treatment measure 1), C group (comprehensive treatment measure 1+ amyl ethyl quin ether), D group (comprehensive treatment measure 2), E group (comprehensive treatment measure 2+ amyl ethyl quin ether).Stablize after 30min, B, C, D, E treated animal are through intravenous injection bacterium liquid (2.5 x10
11cFU/kg), A treated animal is through intravenous injection equal-volume normal saline (2.5ml/kg), to verify the impact on result of anaesthetic and experimental implementation.After thalline is attacked, mean arterial pressure decline 30% is considered as reaching shock standard.
B, C group row endotracheal intubation, tracheal intubation is connected with animal respirator, adjust animal respirator, making its tidal volume is 30ml, respiratory frequency is 30 beats/min, inhaling air oxygen concentration is 100%, and the speed of pressing 25ml/kg/h is through right lateral thigh venous duct input compound NaCl+dopamine hydrochloride (hydrochloric dopamine 1.2mg/kg), continues infusion 2h.D, E group is pressed the speed of 25ml/kg/h through right lateral thigh venous duct input penicillin sodium+compound NaCl+dopamine hydrochloride (containing penicillin sodium 20mg/kg, dopamine hydrochloride 1.2mg/kg), continues infusion 2h.A group is pressed the speed of 25ml/kg/h through right lateral thigh venous duct input normal saline, continues infusion 2h.Infusion starts after 30min, and C, E group give amyl ethyl quin ether through ear vein, and A, B, D group give equal-volume normal saline, and administration volume is 10ml/kg.Respectively at through before ear vein administration, after administration after 30min, administration after 60min, administration after 90min, administration 120min observe above microcirculation index and change.
Statistical method: arteriole caliber, arteriole flow velocity, point of intersect of the capillary network counting and CO
2tension force is measurement data, the one factor analysis of variance method that application SPSS 11.0 softwares provide.
Statistical procedures: application SPSS 10.0 for windows softwares carry out statistical procedures, all data with " mean ± standard deviation (
) " represent.The relatively employing one factor analysis of variance of many group sample averages: first each group data are carried out to normal state check, while meeting normal distribution, adopt one factor analysis of variance (ONE-WAY ANOVA), while not meeting, adopt non parametric tests (Nonparametric Tests).The concrete steps of every observation index and derivation parameter being carried out to 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 (after=administration, certain time point refers to target value/normal value or basic value, lower same) carries out between group variable analysis or non parametric tests relatively judges its significance.
p<0.05 is that difference has significant statistical significance,
p<0.01 is the statistical significance that difference has highly significant.
Table 1 respectively organize rabbit arteriole caliber change (
, n=10)
Note: B, C, D, E group compare with A group, *
p<0.05, * *
p<0.01; C group compares with B group,
△ p<0.05,
△ △ p<0.01; E group compares with D group,
▲ p<0.05,
▲ ▲ p<0.01.
Table 2 respectively organize rabbit arteriole change in flow (
, n=10)
Note: B, C, D, E group compare with A group, *
p<0.05, * *
p<0.01; C group compares with B group,
△ p<0.05,
△ △ p<0.01; E group compares with D group,
▲ p<0.05,
▲ ▲ p<0.01.
Table 3 respectively organize rabbit point of intersect of the capillary network change in count (
, n=10)
Note: B, C, D, E group compare with A group, *
p<0.05, * *
p<0.01; C group compares with B group,
△ p<0.05,
△ △ p<0.01; E group compares with D group,
▲ p<0.05,
▲ ▲ p<0.01.
Table 4 is respectively organized rabbit CO
2tension variation (
, n=10)
Note: B, C, D, E group compare with A group, *
p<0.05, * *
p<0.01; C group compares with B group,
△ p<0.05,
△ △ p<0.01; E group compares with D group,
▲ p<0.05,
▲ ▲ p<0.01.
Result shows: rabbit infects toxic shock and still exists in the situation of microcirculation disturbance through comprehensive treatment measures such as replenishment of blood content, and application amyl ethyl quin ether hydrochloride can obviously be expanded blood capillary, reduces blood viscosity, significantly improve Rabbit Mesentery microcirculation disturbance (
p<0.01).
Claims (2)
1. still there is the application of the situation of microcirculation disturbance in treatment infection toxic shock in amyl ethyl quin ether hydrochloride through comprehensive treatment measures such as replenishment of blood content.
2. administering mode is intramuscular injection and intravenously administrable.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1739511A (en) * | 2002-08-16 | 2006-03-01 | 成都力思特制药股份有限公司 | Application of penehyliclidine hydrochloride in preparing medicine |
| CN101461807A (en) * | 2009-01-15 | 2009-06-24 | 成都力思特制药股份有限公司 | Application of penehyclidine hydrochloride in preparing medicament for treating haemorrhagic shock |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1739511A (en) * | 2002-08-16 | 2006-03-01 | 成都力思特制药股份有限公司 | Application of penehyliclidine hydrochloride in preparing medicine |
| CN101461807A (en) * | 2009-01-15 | 2009-06-24 | 成都力思特制药股份有限公司 | Application of penehyclidine hydrochloride in preparing medicament for treating haemorrhagic shock |
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Effective date of registration: 20210510 Address after: 121013 No. 55 Songshan Street, Taihe District, Jinzhou City, Liaoning Province Patentee after: Jinzhou Aohong Pharmaceutical Co.,Ltd. Address before: 610063 Jinjiang Industrial Development Zone, Sichuan, Chengdu Patentee before: CHENGDU LIST PHARMACEUTICAL Co.,Ltd. |