CN105030782A - Tetrodotoxin compound preparation with anti-arrhythmic effect and preparation method thereof - Google Patents
Tetrodotoxin compound preparation with anti-arrhythmic effect and preparation method thereof Download PDFInfo
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- CN105030782A CN105030782A CN201510481076.5A CN201510481076A CN105030782A CN 105030782 A CN105030782 A CN 105030782A CN 201510481076 A CN201510481076 A CN 201510481076A CN 105030782 A CN105030782 A CN 105030782A
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Abstract
The invention discloses a safe and efficient tetrodotoxin compound preparation with the anti-arrhythmic effect and a preparation method thereof. The tetrodotoxin compound preparation comprises tetrodotoxin, lidocaine hydrochloride, cosolvents, freeze-drying excipients and stabilizing agents. The freeze-drying excipients are mannitol. The stabilizing agents are dextran or beta-cyclodextrin. The cosolvents are citron acid. The preparation can remarkably reduce the death rate caused by rat aconitine model arrhythmia, is particularly suitable for rescuing severe-case arrhythmia patients and can be used for developing new anti-arrhythmic drugs. The preparation is stable in quality, efficient during clinical use and good in safety performance.
Description
Technical field
The present invention relates to drug preparation technique and application, be specifically related to a kind of Fugu ocellatus toxin compound preparation with antiarrhythmic effect and preparation method thereof.
Background technology
Fugu ocellatus toxin is a kind of amino perhydrogenate quinazoline compound, is high selectivity voltage-dependent sodium (Na
+) channel blocker, the arrhythmia that its pharma-toxicology effect mainly contains analgesia, collaborative anesthesia, antagonism aconitine, quinoline Ba Yin etc. cause, suppress the cardiac functions such as heart rate, myocardial contraction and cardiac output, make blood pressure drops, breathe and slow down.The main mechanism of Fugu ocellatus toxin antiarrhythmic effect may be the sodium channel blocking effect due to Fugu ocellatus toxin, the maximum depolarization speed of myocardial cell membrane and fast responsive cells film is significantly reduced, thus reduce the self-disciplining of fast response tissue, make delayed conduction and prolonged refractory period.
Li Mi etc. have studied the Arrhythmia that Fugu ocellatus toxin agonist drug brings out, and result proves that Fugu ocellatus toxin has good antagonism to conventional arrhythmia model, particularly Be very effective in quivering in anti-room.But because the toxicity of Fugu ocellatus toxin is comparatively large, safety range is narrower, the anti-mouse chloroform room therapeutic index that quivers is only 3.2.
Zhu Chenghua etc. have studied the impact of Fugu ocellatus toxin on anti-arrhythmic curative effect and toxicity.Result shows, Fugu ocellatus toxin and conventional anti-arrhythmic vasolan or propranolol share and can significantly improve mice BaCl
2type arrhythmia curative effect; Fugu ocellatus toxin and lignocaine share, and significantly can strengthen rat aconitine model arrhythmia curative effect, thus therapeutic index is significantly improved.
Above-mentioned result of study is that the exploitation of Fugu ocellatus toxin antiarrhythmic drug provides important scientific basis, but because Fugu ocellatus toxin activity is high, toxicity is large, therapeutic index is low, seriously constrain its clinically research application, so far still end have related application in the patent report of antiarrhythmic drug.Though particularly lidocaine hydrochloride is conventional antiventricular arrhythmics, is used alone less effective, easily occurs digestive tract and nervous system untoward reaction during heavy dose of use, also can increase the weight of cardiac insufficiency.Therefore, study micro-Fugu ocellatus toxin with lower than the interaction of common dose lidocaine hydrochloride, development Fugu ocellatus toxin compound preparation, minimumly has major application to strengthen arrhythmia curative effect and to make its toxicity be restricted to and is worth.
Summary of the invention
The object of the present invention is to provide a kind of preparation method with the micro-Fugu ocellatus toxin compound preparation of antiarrhythmic effect; the freeze-dried powder of preparation has the mortality rate significantly reducing rat aconitine model arrhythmia and cause; be particularly suitable for the rescue to serious symptom patients with arrhythmia; and said preparation quality stability is good; Clinical practice is convenient, safety, and compliance is good.
For achieving the above object, solution of the present invention is:
There is a Fugu ocellatus toxin compound preparation for antiarrhythmic effect, containing Fugu ocellatus toxin, lidocaine hydrochloride, cosolvent, freeze-dried excipient and stabilizing agent in its formula; Described freeze-dried excipient is mannitol and dextran; Described stabilizing agent is dextran or beta-schardinger dextrin-; Described cosolvent is citric acid.
The content of described Fugu ocellatus toxin is the every dosage of 0.05 μ g to 5 μ g.
The content of described lignocaine is the every dosage of 1mg to 10mg.
The content of described excipient mannitol is the every dosage of 1mg to 30mg.
The content of described stabilizing agent dextran is the every dosage of 1mg to 30mg.
The content of described stabilizing agent beta-schardinger dextrin-is the every dosage of 1mg to 30mg.
The content of described citric acid is the every dosage of 0.2 μ g to 40 μ g.
Described preparation administering mode is intramuscular injection or subcutaneous injection.
Have a preparation method for the Fugu ocellatus toxin compound preparation of antiarrhythmic effect, it comprises the steps:
Step 1, the Fugu ocellatus toxin of scheduled volume, lidocaine hydrochloride being dissolved in and comprising in the solution of cosolvent, is 3.5-5.0 by citric acid adjust ph, ultrafiltration depyrogenation;
Step 2, the freeze-dried excipient of scheduled volume and stabilizing agent are dissolved in water for injection, add active carbon insulated and stirred 30 minutes at 60-65 DEG C, filter depyrogenation;
Step 3, solution step 1 and step 2 obtained merge mix homogeneously, and through 0.22 μm of filtering with microporous membrane, quantitative filling is in cillin bottle, and vacuum lyophilization, obtains injection Fugu ocellatus toxin compound preparation.
Compound preparation of the present invention has heightening the effect of a treatment, reduces the remarkable advantages such as toxic and side effects compared with folk prescription medicine.Meanwhile, compound preparation have easy to use, patient compliance good and the advantage such as relative low price.
Fugu ocellatus toxin crystal is to thermally-stabilised, but its aqueous solution is to thermally labile.For improving the stability of Fugu ocellatus toxin, in clinical research, often make freeze-dried powder.Lidocaine hydrochloride is white crystalline powder, Stability Analysis of Structures, and common formulations is injection clinically.The present invention with the low micro-Fugu ocellatus toxin of clinical safety using dosage with lower than the lidocaine hydrochloride of clinical usual amounts for main component, be aided with suitable excipient and freeze-dried powder developed by stabilizing agent.Said preparation has the mortality rate significantly reducing rat aconitine model arrhythmia and cause, and is particularly suitable for the rescue to serious symptom patients with arrhythmia.In addition, said preparation quality stability is good, and Clinical practice is convenient, safety, and compliance is good.
Detailed description of the invention
Present invention is disclosed a kind of Fugu ocellatus toxin compound preparation with antiarrhythmic effect, containing Fugu ocellatus toxin, lidocaine hydrochloride, cosolvent, freeze-dried excipient and stabilizing agent in its formula; Described freeze-dried excipient is mannitol and dextran; Described stabilizing agent is dextran or beta-schardinger dextrin-; Described cosolvent is citric acid.Wherein the content of Fugu ocellatus toxin is the every dosage of 0.05 μ g to 5 μ g, preferably the every dosage of 0.5 μ g to 1 μ g; Wherein the content of lidocaine hydrochloride is the every dosage of 1mg to 10mg, the every dosage of preferred 3mg to 5mg; Wherein the content of excipient mannitol is the every dosage of 1mg to 30mg, the every dosage of preferred 6mg to 10mg; Wherein the content of stabilizing agent dextran is the every dosage of 1mg to 30mg, the every dosage of preferred 4mg to 10mg; Wherein dextran is both as stabilizing agent, has the effect of excipient concurrently simultaneously, and its content is the every dosage of 10mg to 30mg, the every dosage of preferred 10mg; Wherein the content of stabilizing agent beta-schardinger dextrin-is the every dosage of 1mg to 30mg, the every dosage of preferred 4mg to 10mg; Wherein the content of citric acid is the every dosage of 0.2 μ g to 40 μ g.Its administering mode is intramuscular injection or subcutaneous injection.
The described concrete steps with the preparation method of the Fugu ocellatus toxin compound preparation of antiarrhythmic effect are:
(1) Fugu ocellatus toxin of scheduled volume, lidocaine hydrochloride being dissolved in and comprising in the solution of cosolvent, is 3.5-5.0 by citric acid adjust ph, ultrafiltration depyrogenation;
(2) freeze-dried excipient of scheduled volume and stabilizing agent are dissolved in water for injection, add active carbon insulated and stirred 30 minutes at 60-70 DEG C, filter depyrogenation;
(3) solution (1) and (2) obtained merges mix homogeneously, and through 0.22 μm of filtering with microporous membrane, quantitative filling, in cillin bottle, is partly jumped a queue, vacuum lyophilization, and Zha Gai after tamponade obtains injection freeze-dried powder.
Below in conjunction with specific embodiment, the present invention is elaborated, but this should be interpreted as that technical solution of the present invention is only limitted to following examples.
Embodiment 1 prescription 1
Preparation method:
(1) Fugu ocellatus toxin of recipe quantity is got, after adding 0.1% citric acid solution 10ml dissolving, add the lidocaine hydrochloride of recipe quantity, inject and be mixed with water 250ml dilution, be 3.5-5.0 by 0.1% citric acid adjust ph, ultrafiltration depyrogenation obtains component A solution;
(2) get mannitol and the beta-schardinger dextrin-of recipe quantity, add water for injection 200ml and dissolve, add active carbon insulated and stirred 30 minutes at 60-65 DEG C, filter depyrogenation and obtain B component solution;
(3) component A solution and B component solution are merged mix homogeneously, be 3.5-5.0 by 0.1% citric acid adjust ph, inject and be settled to 500ml with water, through 0.22 μm of filtering with microporous membrane, after filtrate sampling detection pH value, clarity, content etc. are qualified, aseptic quantitatively (in Fugu ocellatus toxin 1 μ g/ bottle) fill is in cillin bottle, partly jump a queue, vacuum lyophilization, Zha Gai after tamponade, obtains injection Fugu ocellatus toxin compound preparation.
Embodiment 2 prescription 2
Preparation method:
(1) Fugu ocellatus toxin of recipe quantity is got, after adding 0.1% citric acid solution 10ml dissolving, add the lidocaine hydrochloride of recipe quantity, inject and be mixed with water 250ml dilution, be 3.5-5.0 by 0.1% citric acid adjust ph, ultrafiltration depyrogenation obtains component A solution;
(2) get mannitol and the Dextran 40 of recipe quantity, add water for injection 200ml and dissolve, add active carbon insulated and stirred 30 minutes at 60-65 DEG C, filter depyrogenation and obtain B component solution;
(3) component A solution and B component solution are merged mix homogeneously, be 3.5-5.0 by 0.1% citric acid adjust ph, inject and be settled to 500ml with water, through 0.22 μm of filtering with microporous membrane, after filtrate sampling detection pH value, clarity, content etc. are qualified, aseptic quantitatively (in Fugu ocellatus toxin 1 μ g/ bottle) fill is in cillin bottle, partly jump a queue, vacuum lyophilization, Zha Gai after tamponade, obtains injection Fugu ocellatus toxin compound preparation.
Embodiment 3 prescription 3
Preparation method:
(1) get a certain amount of Fugu ocellatus toxin add 0.1% citric acid solution 10ml dissolve after, get the Fugu ocellatus toxin solution (the 0.1% citric acid solution containing 50 μ g Fugu ocellatus toxin) of recipe quantity, add the lidocaine hydrochloride of recipe quantity, inject and be mixed with water 250ml dilution, be 3.5-5.0 by 0.1% citric acid adjust ph, ultrafiltration depyrogenation obtains component A solution;
(2) get mannitol and the Dextran 40 of recipe quantity, add water for injection 200ml and dissolve, add active carbon insulated and stirred 30 minutes at 60-65 DEG C, filter depyrogenation and obtain B component solution;
(3) component A solution and B component solution are merged mix homogeneously, be 3.5-5.0 by 0.1% citric acid adjust ph, inject and be settled to 500ml with water, through 0.22 μm of filtering with microporous membrane, after filtrate sampling detection pH value, clarity, content etc. are qualified, aseptic quantitatively (in Fugu ocellatus toxin 0.05 μ g/ bottle) fill is in cillin bottle, partly jump a queue, vacuum lyophilization, Zha Gai after tamponade, obtains injection Fugu ocellatus toxin compound preparation.
Embodiment 4 prescription 4
Preparation method:
(1) Fugu ocellatus toxin of recipe quantity is got, after adding 0.1% citric acid solution 10ml dissolving, add the lidocaine hydrochloride of recipe quantity, inject and be mixed with water 250ml dilution, be 3.5-5.0 by 0.1% citric acid adjust ph, ultrafiltration depyrogenation obtains component A solution;
(2) get mannitol and the beta-schardinger dextrin-of recipe quantity, add water for injection 200ml and dissolve, add active carbon insulated and stirred 30 minutes at 60-65 DEG C, filter depyrogenation and obtain B component solution;
(3) component A solution and B component solution are merged mix homogeneously, be 3.5-5.0 by 0.1% citric acid adjust ph, inject and be settled to 500ml with water, through 0.22 μm of filtering with microporous membrane, after filtrate sampling detection pH value, clarity, content etc. are qualified, aseptic quantitatively (in Fugu ocellatus toxin 5 μ g/ bottle) fill is in cillin bottle, partly jump a queue, vacuum lyophilization, Zha Gai after tamponade, obtains injection Fugu ocellatus toxin compound preparation.
In order to illustrate that described tetrodotoxin formulation has the effect of antiarrhythmic effect, following pharmacological evaluation is adopted to be illustrated:
Experimental technique
SD rat (200-250g, male and female half and half) is raised in SPF environment after buying, and adapts to start experiment after 3 days.Rat is divided into 5 groups at random, model control group, prescription 1 group, prescription 2 groups, prescription 3 groups, prescription 4 groups.Rats by intraperitoneal injection 20% urethane 1.2g/kg anaesthetizes, and faces upward position and fixes, and it is subcutaneous that needle-like electrode inserts extremity, record standard limb leads II lead electrocardiogram (electrocardiogram, ECG), first screen according to animal electrocardiogram, discard electrocardiographic abnormality animal.After the rhythm of the heart is stable, jugular vein test medicine 0.2ml/200g, 10 μ g/ml, after 2-5min, are injected aconitine 35 μ g/kg in tail vein/external jugular vein constant speed (0.2ml/min) by model group injecting normal saline, continue record ECG.After typical frequent premature ventricular beats occurs, show modeling success.Evaluation index is divided into two aspects, analyzing rat arrhythmic event and mortality rate, simultaneously by degree of arrhythmia scoring.
(1) rat ventricular time and mortality rate
Continue the ECG recording every rat, analyzing rat ARR time started, persistent period and mortality rate.The time of appearance first premature beat is arrived as initial time after injecting aconitine; Persistent period deducts the sinus arrhythmia time in the arrhythmia persistent period.
(2) change of arrhythmia scoring
For assessing the ARR order of severity, 6 grades arrhythmia are divided into mark, adopt Curtis-Walker method in conjunction with Mest method, respectively at after quiet note aconitine 5,10,20,30,60min time, mark to arrhythmia, the mark getting its a kind of the most serious arrhythmia corresponding within every period of observing time is marked as its arrhythmia.Standards of grading are as follows: 0 point, without arrhythmia; 1 point, atrial arrhythmia, accidental room is early; 2 points, room early premature ventricular beat, premature ventricular beat, the room of taking place frequently early, second degree A-V block; 3 points, short battle array room speed, multi-source room is early; 4 points, room speed, third degree A-V block; 5 points, quiver in room, dead.
Statistical procedures
Result X ± SD represents, contrasts t-test and compare between two between employing group, and p<0.05 is for there being significant difference.
Experimental result
(1) change of rat ventricular and mortality rate
As shown in Tab.1, various ventricular arrhythmia is brought out in model group rats ECG display after intravenous injection aconitine, and mortality rate is 53.33%.Non-dead animal statistics arrhythmia initial time and arrhythmia persistent period.Prescription 1 group of ECG shows the initial time significant prolongation of arrhythmia, reverses mortality rate, is reduced to 0 from model control group 53.33%.2 groups of surviving animals arrhythmia persistent period of prescription significantly shorten, and mortality rate is 10.00%.The initial time significant prolongation of arrhythmia of prescription 3 groups of rats, mortality rate is 20.00%; Prescription 4 groups of ECG show the initial time significant prolongation of arrhythmia, and reverse mortality rate, mortality rate is 5.00%.
To sum up, prescription 1 group, prescription 2 groups, prescription 3 groups and prescription 4 groups all can improve the mortality rate that Aconitine Induced rat ventricular causes.
Tab.1 test medicine is on the impact of Aconitine Induced rat ventricular
Note * p<0.05 and model group compare.
(2) comparison of rat ventricular scoring
As shown in Tab.2, rat is after giving aconitine, and arrhythmia occurs heavier and progress is rapid, compares with model control group, and each prescription group is marked except modeling 5min, other times Duan Junneng obviously reduce arrhythmia.
The comparison that Tab.2 test medicine is marked to Aconitine Induced rat ventricular
Note: * p<0.05, * * p<0.01, * * * p<0.001 and model group compare
Conclusion
Compare with model control group, 4 all have antiarrhythmic effect by reagent prescription 1, prescription 2, prescription 3 and prescription 4.
In order to illustrate that described Fugu ocellatus toxin compound preparation quality stability is good, we have carried out stability test research by the sample of 40 DEG C of temperatures involved Factor Experiments to preparation.As shown in Tab.3, each prescription group sample is placed 5 days, 10 days at 40 DEG C, and sample property is without significant change, and content, within the scope of quality standard, illustrates that the Fugu ocellatus toxin compound preparation quality stability of preparation is good.
Tab.340 DEG C of temperatures involved factorial experiments result
Claims (9)
1. there is a Fugu ocellatus toxin compound preparation for antiarrhythmic effect, it is characterized in that: it contains Fugu ocellatus toxin, lidocaine hydrochloride, cosolvent, freeze-dried excipient and stabilizing agent; Described freeze-dried excipient is mannitol; Described stabilizing agent is dextran or beta-schardinger dextrin-; Described cosolvent is citric acid.
2. there is the Fugu ocellatus toxin compound preparation of antiarrhythmic effect as claimed in claim 1, it is characterized in that: the content of described Fugu ocellatus toxin is the every dosage of 0.05 μ g to 5 μ g.
3. there is the Fugu ocellatus toxin compound preparation of antiarrhythmic effect as claimed in claim 1, it is characterized in that: the content of described lignocaine is the every dosage of 1mg to 10mg.
4. there is the Fugu ocellatus toxin compound preparation of antiarrhythmic effect as claimed in claim 1, it is characterized in that: the content of described excipient mannitol is the every dosage of 1mg to 30mg.
5. there is the Fugu ocellatus toxin compound preparation of antiarrhythmic effect as claimed in claim 1, it is characterized in that: the content of described stabilizing agent dextran is the every dosage of 1mg to 30mg.
6. there is the Fugu ocellatus toxin compound preparation of antiarrhythmic effect as claimed in claim 1, it is characterized in that: the content of described stabilizing agent beta-schardinger dextrin-is the every dosage of 1mg to 30mg.
7. there is the Fugu ocellatus toxin compound preparation of antiarrhythmic effect as claimed in claim 1, it is characterized in that: the content of described citric acid is the every dosage of 0.2 μ g to 40 μ g.
8. the Fugu ocellatus toxin compound preparation with antiarrhythmic effect as described in any one of claim 1 to 7, is characterized in that: described preparation administering mode is intramuscular injection or subcutaneous injection.
9. have a preparation method for the Fugu ocellatus toxin compound preparation of antiarrhythmic effect, it comprises the steps:
Step 1, the Fugu ocellatus toxin of scheduled volume, lidocaine hydrochloride being dissolved in and comprising in the solution of cosolvent, is 3.5-5.0 by citric acid adjust ph, ultrafiltration depyrogenation;
Step 2, the freeze-dried excipient of scheduled volume and stabilizing agent are dissolved in water for injection, add active carbon insulated and stirred 30 minutes at 60-65 DEG C, filter depyrogenation;
Step 3, solution step 1 and step 2 obtained merge mix homogeneously, and through 0.22 μm of filtering with microporous membrane, quantitative filling is in cillin bottle, and vacuum lyophilization, obtains injection Fugu ocellatus toxin compound preparation.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1470515A (en) * | 2003-06-24 | 2004-01-28 | 中国海洋大学 | Method for extracting tetrodotoxin from globefish livers |
| CN1736380A (en) * | 2004-08-20 | 2006-02-22 | 厦门一元生物工程有限公司 | Drug addiction-stopping formulation and preparation thereof |
| CN101352422A (en) * | 2008-09-17 | 2009-01-28 | 厦门朝阳生物工程有限公司 | Tetrodotoxin lyophilized powder formulation for injection and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1470515A (en) * | 2003-06-24 | 2004-01-28 | 中国海洋大学 | Method for extracting tetrodotoxin from globefish livers |
| CN1736380A (en) * | 2004-08-20 | 2006-02-22 | 厦门一元生物工程有限公司 | Drug addiction-stopping formulation and preparation thereof |
| CN101352422A (en) * | 2008-09-17 | 2009-01-28 | 厦门朝阳生物工程有限公司 | Tetrodotoxin lyophilized powder formulation for injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 李蕴山等: "河鲀毒素协同戊脉安、利多卡因、心得安抗大鼠缺血性心律失常作用观察", 《河北渔业》 * |
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Application publication date: 20151111 |