CN103463080B - Guanfu Base S is as the application of preparation treatment antiarrhythmic medicament - Google Patents
Guanfu Base S is as the application of preparation treatment antiarrhythmic medicament Download PDFInfo
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Abstract
The invention discloses the application of Guanfu Base S as preparation treatment antiarrhythmic medicament.Guanfu Base S can obviously block guinea pig cardiomyocytes sodium-ion channel, Be very effective, and it provides potential application prospect for treating irregular heart pulse medicine.
Description
Technical field
The present invention relates to the application of Guanfu Base S, especially prepare the application in antiarrhythmic medicament.
Background technology
Guanfu Base S (GuanfuBaseS), belongs to native compound, its molecular formula: C
24h
29nO
5, molecular weight: 401.21.Up to the present, Guanfu Base S is only separated and obtains in Ranunculaceae aconitum plant Radix Aconiti Coreani, CAS accession number: 1037700-00-7, and structural formula is as follows:
Chinese medicine Radix Aconiti Coreani is the tuber of Ranunculaceae aconitum plant Radix Aconiti Coreani Aconitumcoreanum (Levl) Rapaics.Ancient times, diseases such as curing mainly pained arthralgia due to stagnation of blood, migraine, cold warm arthralgia pain recorded by book on Chinese herbal medicine; Pharmacology proves that some compositions wherein have antiarrhythmic effect.Containing Guanfu Base S in the tuber of Radix Aconiti Coreani.
Arrhythmia (CardiacArrhythmia) refers to rhythm of the heart origin position, cardiac frequency in any one such as the rhythm and pace of moving things and conduction of impulse extremely, is one of clinical common disease.Arrhythmia can occur in healthy population, more often occurs in the patient of organic heart disease and congestive heart failure.With regard to the mechanism that arrhythmia occurs, mainly impulsion forms abnormal (the abnormal and activity of setting out of self-disciplining, all can cause abnormal granting of getting excited) and conduction of impulse extremely, and the arrhythmia of some type may exist two kinds of situations simultaneously.Common arrhythmia has sinus tachycardia, sinus bradycardia, arrhythmia, premature beat, paroxysmal tachycardia, atrial fibrillation, atrioventricular block etc.Cause ARR reason to have a lot, common are cardiovascular disease, electrolyte disturbance, drug effect, infection and virus function, neural factors, endocrine factors etc.Clinical is its main manifestations with cardiopalmus, uncomfortable in chest, dizzy, hypotension, perspiration, and fainting can appear in severe patient, even dies suddenly.
ARR pathogenesis is relevant with the exception of Single Cardiac Cell process of repolarization, and main manifestations is myocardial action potential repolarization time lengthening and process of repolarization heterogeneity.In the formation of Single Cardiac Cell, sodium channel, calcium channel and ultrarapid delayed rectifier potassium channel important role, how associated antiarrhythmic drug is also.Anti-arrhythmic is often divided into four classes: I class blocks the sodium channel of cardiac muscle and conducting system of heart, has membrane stabilizing action, and reduce action potential 0 phase depolarization climbing speed and amplitude, slow down conduction velocity, extends APD and ERP.On resting membrane electric potential without impact.Sodium channel is the main depolarization current that myocardial cell generation action potential is, when cardiac muscle cells is upset, depolarization is to the threshold potential of sodium channel, and then formation action potential is activated in sodium channel, this produces new stimulation to adjacent cells, thus action excitement is conducted.Medicine can to slow down the generation of action potential and conduction to the suppression of the activated state of sodium channel, decreased heart rate, stabilizing cell membrane, thus suppresses ARR generation.The inactivation of sodium channel has two kinds of processes, and a kind of is the rapid deactivation of stable state, and this process is termination action potential, and another kind is slow inactivation, portion of channel can continuous openness to the action potential later stage, form late Na current.In pathological state, as myocardial ischemia, myocardial hypertrophy, in atrial fibrillation, late Na current can strengthen.Sodium ion inflow is too much, thus sodium Calcium exchanger is strengthened, causes intracellular calcium overload, increases the weight of myocardial damage, calcium too much in born of the same parents and then understand effect string mitochondria function thus affect the metabolism of cell, increases the weight of cell injury, over reach potential duration.Effectively can must shorten the action potential of myocardial cell to its suppression and alleviate myocardial damage thus treatment arrhythmia.
There is bibliographical information Radix Aconiti Coreani total alkaloid salt (GFI, 2.7%, GFA, 82.9%) effectively can resist atrial fibrillation, improve the electricity reconstruct that atrial fibrillation causes.Radix Aconiti Coreani element in the ninth of the ten Heavenly Stems (GFI) itself does not possess antiarrhythmic activity, and Guan-fubase A, on the target spot of retardance ion channel, only shows faint activity to sodium-ion channel, and its mechanism of action need to find as seen.Guanfu Base S is not yet had to disclose as the application of preparation treatment antiarrhythmic medicament in modern technologies.
Summary of the invention
The object of the invention is on the basis of existing technology, a kind of compound that can be applied to treating irregular heart pulse is provided.。
Object of the present invention can be reached by following measures:
The application of Guanfu Base S in preparation treatment antiarrhythmic medicament.
A kind of pharmaceutical composition, said composition take Guanfu Base S as main active or is active component with Guanfu Base S, is aided with pharmaceutically acceptable carrier.
Above-mentioned composition can be oral formulations or non-oral formulation.
When Guanfu Base S is for the preparation for the treatment of antiarrhythmic medicament, its oral or non-oral administration is all safely and effectively.Oral administration can make any regular dosage form, as: powder, granule, capsule, sheet, oral cavity disintegration tablet, drop pill, soft capsule etc.; Non-oral administration, can be made into various regular dosage form, as injection etc.
When Guanfu Base S is for the preparation for the treatment of antiarrhythmic medicament, its adjuvant and preparation method can select the acceptable form of any pharmacy.
The dosage of Guanfu Base S can according to take mode, patient the factor such as age, coincident with severity degree of condition and change, become human oral dosage form to be 1-200mg/ day, adult injection dosage is 1-50mg/ day.
Guanfu Base S has antiarrhythmic activity, can obviously block guinea pig cardiomyocytes sodium-ion channel, Be very effective.Guanfu Base S is that treating irregular heart pulse medicine provides potential application prospect.
Accompanying drawing explanation
Fig. 1 is the map of current of sodium current test.
Fig. 2 is the concentration dependent inhibition test result figure of Guanfu Base S to sodium current.
Fig. 3 is the voltage-dependent inhibition test result figure of Guanfu Base S to sodium current.
Fig. 4 is that Guanfu Base S affects result of the test figure to the stable state activation parameter of passage.
Fig. 5 is that Guanfu Base S affects result of the test figure to sodium channel Steady-state inactivation parameter.
Detailed description of the invention
Guanfu Base S treats ARR effect, is embodied by following test:
Test example 1, Guanfu Base S are on the impact of guinea pig cardiomyocytes sodium-ion channel
1, material
1.1 medicines extract the Guanfu Base S obtained from the tuber of Ranunculaceae aconitum plant Radix Aconiti Coreani Aconitumcoreanum (Levl) Rapaics, and separation obtains 18 diterpene alkaloid compound (hetisine from Radix Aconiti Coreani total alkaloid salt, Guan-fubase A, Guanfu base H, pass Radix Aconiti Lateralis Preparata element, Radix Aconiti Coreani noon element, Guan-fubase B, condelphine, acrodine, Radix Aconiti Coreani element in the ninth of the ten Heavenly Stems, Radix Aconiti Coreani amine alcohol, Radix Aconiti Coreani Z element, mesaconitine, hypaconitine, dihydroatisine, 2-isobutryl-14-hydroxy-hetisineN-oxide, Radix Aconiti Coreani V element, Radix Aconiti Coreani X-ogen, Talatisamine, HEPES, collagenase II type (the raw work in Shanghai), Na
2-ATP, EGTA, CsF, CsCl, CoCl
2(Sigma).
1.2 animal Cavia porcelluss, male, body weight 300 ± 50g, Qinglongshan animal cultivation field, Jiangning provides.
1.3 instrument
1.4 experimental solutions preparations
1. without calcium tyrode's solution (mmol/L): NaCl137.0, KCl5.4, MgCl
21.2, glucose 10.0, HEPES10.0, taurine 10.0, regulates pH to be 7.4 with NaOH.
2. enzyme is contained without calcium tyrode's solution (mmol/L): add bovine serum albumin 1.0mg/mL without in calcium tyrode's solution, collagenase II type 0.3mg/mL, regulate pH to be 7.4 with NaOH.
3. KB liquid (mmol/L): KOH70.0; KCl40.0, KH
2pO
420.0, glutamic acid 50.0, MgCl
23.0, taurine 20.0, EGTA0.5, HEPES10.0, glucose 10.0, regulates pH to be 7.4 with KOH.
4. liquid (mmol/L) in electrode: CsF110.0, CsCl20.0, MgCl
23.0, NaCl10.0, Na
2-ATP5.0, EGTA10.0, HEPSE5.0, regulate pH to 7.2 with CsOH
5. extracellular fluid: add CsCl5.0mmol/L without calcium tyrode's solution, CoCl
23.0mmol/L, CaCl
21.0mmol/L.
2, experimental technique
2.1 myocardial cell are separated normal guinea pig, and (male and female are not limit, 300 ± 20g) lumbar injection 10% chloral hydrate solution (0.3ml/100g body weight) anesthesia, lie on the back fixing, thoracic cavity is cut off in center, rapid taking-up heart, puts into 0-4 DEG C without calcium tyrode, by aorta, heart is hung on Langendorff device after pruning, with 37 ° of C without calcium tyrode's solution constant temperature perfusion, flow velocity 6 ~ 8mL/min.Perfusion is about 5min, change containing enzyme without calcium Zinciodati Comp solution perfusion about 10 ~ 15min after cleaning congestion, until cardiac muscle present expand loose and translucent time, cut left ventricle, blow and beat gently with glass dropper in KB liquid, filter, can band be obtained clear, the bar-shaped Ventricular Myocytes of any surface finish, is kept in KB liquid.All experiment solution all uses 95%O
2+ 5%CO
2saturated.
2.2 Cell Culture Cells recoveries, liquid nitrogen takes out cell in filling with, and 37 ° of C water-baths are thawed, and puts into superclean bench after spraying alcohol disinfecting.Cryopreserving liquid is transferred to T-75flask, adds Ham ' the sF12 culture medium of cryopreserving liquid 10-15 times amount containing 15-20%FBS, piping and druming evenly, after 37 ° of C constant-temperature incubation 8-16h, is removed suspension cell, is added fresh culture.Within 1-2 days, change liquid once.Every day changes liquid.7-10d cell grows to bottom culture bottle and can go down to posterity more than 80% area, enzyme liquid digestion 3-5min, and basis of microscopic observation cell edges is shunk, cell separation becomes individual cells, adds and stops digestion containing blood serum medium, and pipettor is drawn culture medium and blown and beaten a bottle wall gently, cell is made to take off wall, suspended dispersed.Add times amount culture medium, evenly, subpackage mixed liquor, amplification of going down to posterity, cultivates under the same condition in piping and druming.
2.3 Whole-cell recording methods, for cultured cells, are sub-packed in little Tissue Culture Dish when once going down to posterity before use, sealing is put in incubator, carries out patch clamp experiments for adherent rear taking-up.Use the culture medium leaned forward out in ware, add extracellular fluid.For the myocardial cell of acute isolation, get appropriate in small beaker before using, leave standstill and make cell precipitation, careful sucking-off KB liquid, adds extracellular fluid.For the extracellular fluid of calcic, liquid to be changed according to calcium concentration gradient.Draw a small amount of cell suspension after changing liquid and be placed in little cell circumstances ware, after adherent, carry out patch clamp experiments.Tissue Culture Dish is placed on inverted microscope object stage, after cell attachment, uses slight manipulator to be placed near cell by the dosing mouth of gravity drug-supplying system, use the outer liquid perfusion of normal cell.The glass microelectrode used in experiment draws instrument two step through microelectrode and draws, and uses the process of polishing electrode instrument to make most advanced and sophisticated smooth, choose filling enter water with liquid in electrode after resistance value test for the electrode of 2-5M Ω.Three-dimensional narishige is regulated to make eletrode tip shift to cell, and gently press cell surface, giving certain negative pressure makes eletrode tip and cell surface form the high resistance seals of more than G Ω, compensate fast electric capacity to eliminating electric capacity wink mark, give larger negative pressure again and inhale broken cell film, form whole-cell recording technique pattern, compensate slow electric capacity and series resistance, eliminate electric capacity wink mark as far as possible.The signal of telecommunication guides through Ag/AgCl electrode, is amplified, send to computer through data collecting card by patch clamp amplifier, and computer carries out stimulation by Pulse program and provides and signals collecting, and data are stored in hard disc of computer.All experiments are all carried out under room temperature (23 ~ 25 DEG C).During record current, first to cell with the outer liquid perfusion 5min of normal cell, the electric current obtained is as control.Then the extracellular fluid of concentration perfusion pastille from low to high successively, first concentration gives record current after 5min.
3, experimental result
The outer liquid of observation of cell of 3.1 sodium currents uses tyrode's solution.By cell clamp on the maintenance current potential of-90mV, give the depolarization of-40mV of 100ms, draw sodium current, perfusion to continue after 5min record again to the Guanfu Base S of 3 μMs, and the electric current after being inhibited is as Fig. 1.
It is as follows that 3.2 Guanfu Base S give Guanfu Base S concentration after suppressing to be recorded to sodium current to the concentration dependent of sodium current successively: 1 μM, 3 μMs, the Concentraton gradient of 10 μMs and 30 μMs, record gives the electric current after each concentration, calculates suppression ratio Inhibition=(Icontrol-I administration)/* 100/Icontrol.Suppression ratio divides concentration maps and uses Hill equation model to calculate IC
50, y=x^n/ (k^n+x^n), wherein y is suppression ratio, and x is drug level, and parameter k is half-inhibition concentration IC
50, n is the slope of curve.Result is as Fig. 2, IC
50be 3.48 ± 1.08 μMs (n=5).
3.3 Guanfu Base S suppress cell clamp on the maintenance current potential of-90mV the voltage-dependent of sodium current, give from-70mV, and a series of depolarizations of step 5mV to+40mV stimulate, frequency is 1Hz.Obtain the I-V curve of sodium current.Perfusion gives the Guanfu Base S of 3 μMs, again record, draws the voltage-dependent inhibitory action of Guanfu Base S to sodium current, as Fig. 3.
3.4 Guanfu Base S on the impact of the stable state activation parameter of passage with Boltzmann equation model I/Imax=(1+exp [(V-V1/2)/r]).V1/2 is half activation voltage of passage.R is slope.Result is as Fig. 4.Move to left to the stable state activating curve of sodium channel after Guanfu Base S.I under normal condition and under 3 μMs of Guanfu Base S effects
nahalf activation voltage be respectively-51.47 ± 0.31mV(k=2.24 ± 0.28mV) ,-55.21 ± 0.3mV (k=1.39 ± 0.19mV).
3.5 Guanfu Base S on sodium channel Steady-state inactivation parameter affect the stable state activated current of record sodium channel time, ME for maintenance is from-120mV, and with the step of 10mV, continue 500ms, then depolarization is to-40mV at every turn, draws Na electric current.Na current peak is used to map to membrane voltage.Use Boltzmann equation model, draw steady-state inactivation curves.As Fig. 5.Also move to left to the steady-state inactivation curves of sodium channel after Guanfu Base S.I under normal condition and under 3 μMs of Guanfu Base S effects
nahalf inactivation voltage be respectively-83.26 ± 0.25mV(k=5.79 ± 0.22mV) ,-88.86 ± 0.31mV(k=6.14 ± 0.28mV).
Guanfu Base S suppresses sodium channel current in the mode of concentration dependent, IC
50at 3.48 μMs, it can play membrane stabilizing action to the direct suppression of sodium channel, and the irritability reducing cell reduces the possibility of ectopic rhythm generation, thus suppresses arrhythmia.The compound Zhong Jin local authorities noon element (IC obtained is separated from Radix Aconiti Coreani total alkaloid salt
50=82.65 ± 29.56 μMs), hetisine (IC
50=75.72 ± 14.64 μMs), Guan-fubase A (IC
50=41.17 ± 10.32 μMs) and Guan-fubase B (IC
50=23.81 ± 8.42 μMs) show the activity blocking sodium-ion channel, other Compound I C
50value is all greater than 100 μMs.
In sum, Guanfu Base S can effectively suppress guinea pig cardiomyocytes sodium-ion channel, is that it treats ARR pharmacological basis.Embodiment 1
Tablet: Guanfu Base S 10g, starch 190g, granulate, tabletting makes 1000.Instructions of taking: be grown up one time 1,2 times on the one.Embodiment 2
Capsule: Guanfu Base S 10g, starch 190g, mixing, makes 1000.Instructions of taking: be grown up one time 1,2 times on the one.
Claims (1)
1. the application of Guanfu Base S in preparation treatment antiarrhythmic medicament.
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|---|---|---|---|---|
| CN1660088A (en) * | 2005-01-21 | 2005-08-31 | 中国药科大学 | Application of Guan-fubase B hydrochloride in preparing injection for treating yentricular arerhythmias |
| CN1709892A (en) * | 2005-07-06 | 2005-12-21 | 中国药科大学 | Method for preparing total biological alkali extract of korean aconite roof and use |
| CN102697774A (en) * | 2012-06-19 | 2012-10-03 | 中国药科大学 | New application of Korean mondshood root total alkaloids and guanfu base VIIII |
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| CN1660088A (en) * | 2005-01-21 | 2005-08-31 | 中国药科大学 | Application of Guan-fubase B hydrochloride in preparing injection for treating yentricular arerhythmias |
| CN1709892A (en) * | 2005-07-06 | 2005-12-21 | 中国药科大学 | Method for preparing total biological alkali extract of korean aconite roof and use |
| CN102697774A (en) * | 2012-06-19 | 2012-10-03 | 中国药科大学 | New application of Korean mondshood root total alkaloids and guanfu base VIIII |
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| Title |
|---|
| A New Diterpenoid and a New Diterpenoid Alkaloid from Aconitum coreanum;Chun-Hua Yang等;《HELVETICA CHIMICA ACTA》;20081231;第91卷;第759-765页 * |
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