Aconite
1、 Aconite pharmacopoeia standard       This product is the processed product of Aconitum carmichaelii debx., a plant of Ranunculaceae. From late June to early August, it is excavated to remove the mother root, fibrous root and sediment, which is commonly known as "mud aconite", and processed into the following specifications.
      (1) Choose a large and uniform mud aconite, wash it, immerse it in the aqueous solution of gall overnight, add salt, continue to soak it, take it out and dry it every day, and gradually extend the drying time until a large number of crystalline salt particles (salt frost) appear on the surface of aconite, and the body hardens, which is commonly known as "salt aconite".
      (2) Take the mud aconite, wash it according to its size, immerse it in the aqueous solution of gall for a few days, boil it with the immersion solution until it is transparent, take it out, float it, cut it into pieces with a thickness of about 0.5cm longitudinally, then soak it in water, dye the aconite pieces with the toner, take it out, steam it until it has oil surface and luster, bake it to half dry, and then dry it in the sun or continue to dry it, which is commonly known as "tanshun tablets".
      (3) Select mud aconite with uniform size, wash it, immerse it in the aqueous solution of gall for a few days, boil it with the immersion solution until it reaches the heart, take it out, peel off the skin, cut it longitudinally into pieces with a thickness of about 0.3cm, soak it with water, take it out, evaporate it thoroughly, and dry it. It is commonly known as "white aconite tablets".
      [character]   Salt aconite   It is conical in shape, 4 ～ 7cm long and 3 ～ 5cm in diameter. Its surface is gray black, covered with salt frost. There are dented bud marks on the top and nodular protuberant roots or root marks around it. Body weight, taupe cross section, small gaps filled with salt frost and polygonal cambium annuli can be seen, and the inner duct bundles of the annuli are not neatly arranged. .
      Heishun tablets   It is a longitudinal section, which is wide at the top and narrow at the bottom, 1.7 ～ 5cm long, 0.9 ～ 3cm wide and 0.2 ～ 0.5cm thick. The outer skin is dark brown, dark yellow in section, oily and shiny, translucent, and has longitudinal guide bundles. It is hard and brittle with horny section. The air is weak and the taste is light.
      Rhizoma typhonii   No outer skin, yellowish white, translucent, about 0.3cm thick.
      [identification]   . In addition, take benzoyl mesaconitine control, benzoyl aconitine control, benzoyl hypaconitine control, and add isopropanol dichloromethane (1:1) mixed solution to make a mixed solution containing 1mg per 1ml as the control solution (monoester alkaloid). Then take mesaconitine reference, hypaconitine reference, aconitine reference, and add isopropanol dichloromethane (1:1) mixed solution to make a mixed solution containing 1mg per 1ml as the reference solution (diester alkaloid). Test according to thin-layer chromatography (general rule 0502), suck 5-10 μ l of the test solution and the reference solution respectively, dot them on the same silica gel G thin-layer plate, use n-hexane ethyl acetate methanol (6.4:3.6:1) as the developing agent, place in the developing cylinder saturated with ammonia vapor for 20 minutes, develop, take out, air dry, and spray with dilute bismuth potassium iodide test solution. ; Heishun tablets or Baifu tablets show spots of the same color on the corresponding positions of the chromatography with benzoyl mesaconitine control, benzoyl aconitine control and benzoyl hypaconitine control
      [check]   Moisture   Not more than 15.0% (the second method of general rule 0832).
      Diester alkaloids   Test according to the chromatographic conditions and the preparation method of the test solution under [content determination].
      Preparation of reference solution   Take an appropriate amount of mesaconitine reference substance, hypaconitine reference substance and aconitine reference substance, weigh accurately, add isopropanol dichloromethane (1:1) mixed solution to make a mixed solution containing 5 μ g per 1ml.
      ; Precisely suck 10 μ l of the above reference solution and 10 μ l of the test solution under [content determination] respectively, inject them into the liquid chromatograph, and determine.
      The diester alkaloids contained in this product shall not exceed 0.020% based on the total amount of mesaconitine (c33h45no11), hypaconitine (c33h45no10) and aconitine (c34h47no11).
      ; Determine according to high-performance liquid chromatography (general rule 0512).
      ; Octadecylsilane bonded silica gel was used as filler; Acetonitrile tetrahydrofuran (25:15) was used as mobile phase a, 0.1mol/l ammonium acetate solution (0.5ml of glacial acetic acid per 1000ml) was used as mobile phase B, gradient elution was carried out according to the following table, and the detection wavelength was 235nm. The number of theoretical plates according to the peak of benzoyl mesaconitine should not be less than 3000.
    ------------------------------------
        Time (min) mobile phase a (%) mobile phase B (%)
    ------------------------------------
     0～48        15→26     85→74
    48～49        26→35     74→65 
    49～58        35         65   
    58～65        35→15     65→85
    ------------------------------------
      Preparation of reference solution   Take an appropriate amount of benzoyl mesaconitine reference substance, benzoyl aconitine reference substance, benzoyl hypaconitine reference substance, accurately weigh, add isopropanol dichloromethane (1:1) mixed solution to make a mixed solution containing 10 μ g per 1ml.
      Preparation of test solution   Take about 2G of this product powder (passing through No. 3 screen), weigh it accurately, put it into a corked conical flask, add 3ml of ammonia test solution, precisely add 50ml of isopropanol ethyl acetate (1:1) mixed solution, weigh it, sonicate (power 300W, frequency 40KHz, water temperature below 25 ℃) for 30 minutes, cool it, weigh it again, use isopropanol ethyl acetate (1:1) mixed solution to make up the weight lost, shake it well, and filter it. .
      Assay   Precisely suck 10 μ l of the reference solution and 10 μ l of the test solution respectively, inject them into the liquid chromatograph, and determine.
      The total amount of benzoyl mesaconitine (c31h43no10), benzoyl aconitine (c32h45no10) and benzoyl hypaconitine (c31h43no9) in this product shall not be less than 0.010% according to the dry product.
      Decoction pieces
      [processing]   Aconite (heishun tablet, Baifu tablet)   Directly into medicine.
      [character], [identification], [inspection], [content determination]   Same as medicinal materials.
      Light aconite tablets   Take salt aconite, soak and bleach it with clear water, change the water 2-3 times a day, till the salt is bleached out, add water with licorice and black beans, and boil it through to the heart. When there is no tingling and bitter feeling in the mouth after cutting, take it out, remove licorice and black beans, cut thin slices, and dry it in the sun.  
        .
      The product is in longitudinal section, with width at the top and narrow at the bottom, 1.7-5cm long, 0.9-3cm wide and 0.2-0.5cm thick. The skin is brown. . The texture is hard and the cross-section is horny. The breath is slight, the taste is light, and the taste is not numb.
      [check]   Diester alkaloids   For the same medicinal material, the content of diester alkaloids shall not exceed 0.010% based on the total amount of mesaconitine (c33h45no11), hypaconitine (c33h45no10) and aconitine (c34h47no11).
      [identification] [inspection] (moisture) [content determination]   Same as medicinal materials.
      Cannon attached film   .
      This product is shaped like heishunpian or baifupian, with a yellow brown bulge on the surface and a crunchy texture. The air is weak and the taste is light.
      [identification] [inspection]   Same as that in the attached sheet.
      ; . Homing, kidney and spleen meridians.
      ; It can restore yang to rescue adversity, replenish fire to help Yang, dispel cold and relieve pain. It is used for dead Yang collapse, limb cold pulse micro, heart yang deficiency, chest obstruction and heartache, deficiency cold vomiting and diarrhea, abdominal cavity cold pain, kidney yang deficiency and failure, impotence and palace cold, Yin cold edema, Yang deficiency and external sensation, cold dampness and arthralgia.
      [usage and dosage]   3～15g， .
      [note]   Pregnant women should use it with caution; .
      [storage]   Salt aconite is sealed and placed in a cool and dry place; Heishun tablets and Baifu tablets shall be placed in a dry place to prevent moisture.
      Note: only [character] test is conducted for semen Aconiti Lateralis.


2、 Chemical constituents of aconite
Aconite containsAconitine（aconitine），Mesoaconitine（mesaconitine），Hypaconitine（hypaconitine），Talaconitine（talatisamine）， Higenamine is demethylcysteine, coryneine chloride, isodelphinine, benzoyl mesaconitine, neoline,Fuziling（fuziline）， Beiwutine,Aconitine Polygonum（karakoline）， Deoxyaconitine, fuzitine,Quasi Aconitine（songorine）Uracil（uracil）， Jiangyouaconitine, neojiangyouaconitine, salsolinol, etc.

3、 Pharmacological action of aconite
1. anti inflammatory effect and endocrine effect: oral administration of aconite 20% Decoction 2.5ml / 100g or 50% Decoction 2ml / 100g in rats had a very significant inhibitory effect on ankle swelling induced by formaldehyde or egg white in rats (P < 0.01). The 0.5g / kg Decoction of cooked aconite tablets also significantly inhibited egg white foot swelling in rats. The methanol extract of raw aconite can inhibit the increase of peritoneal vascular permeability caused by egg white and the ankle swelling caused by carrageenan in mice. The effect of 300mg / kg oral administration on adjuvant arthritis of ankle joint in rats was stronger than that of 50mg / kg oral administration of butazone. The inhibitory effect of 30mg / kg oral administration on cotton ball granuloma was stronger than that of 20mg / kg oral administration of cortisone. Aconite Decoction alcohol precipitate (2G per 1ml= crude drug) was intraperitoneally injected into rats at different doses, which had different inhibitory effects on egg white joint swelling, and its intensity was positively correlated with the drug dose. There are different views on the mechanism of the anti-inflammatory effect of aconite: if it is reported that after giving aconite, the content of vitamin C and cholesterol in the adrenal gland decreases, the urinary excretion of 17 keto sterols increases, the blood eosinophilic leukocytes decrease, and the alkaline phosphatase and liver glucose do not increase, which seems to have the effect of exciting the pituitary renal supraglandular cortical system. It has also been reported that the anti-inflammatory effect of aconite is still preserved after adrenalectomy, and it is believed that its anti-inflammatory effect is not related to the pituitary adrenal cortex system. Some people believe that aconite itself has glucocorticoid like effects.
2. analgesia, sedation and effect on body temperature: aconite 0.1-1g / kg given to animals can inhibit the pain caused by compressing the tail of rats and the writhing reaction of mice caused by intraperitoneal injection of acetic acid. Aconite Decoction and alcohol precipitate (1ml = 2G crude drug) was intraperitoneally injected into mice, which could improve the pain threshold of mice. Oral administration of aconite cold extract in mice can prolong the sleep time of cyclohexbarbital sodium, reduce spontaneous exercise, and reduce body temperature for up to 2 hours, while processed aconite has no such effect at the same dose. However, in cold conditions, aconite cold extract and water decoction can inhibit the cold induced temperature drop in chickens and rats, and even restore the reduced temperature, prolong survival time and reduce mortality. Aconite Decoction 20g / kg gavage to mice can significantly prolong the survival rate of cold affected mice (P < 0.01). Aconite Decoction can significantly resist water immersion stress in mice and hydrochloric acid injury ulcer in rats; It can also significantly resist the drug-induced diarrhea in mice caused by castor oil and senna leaf, and its analgesic effect in hot plate method, etc., which is considered to be the pharmacological basis of aconite warm pain relief.
3. effect on cardiovascular system:.
3.1. cardiotonic and pressor effects: noraconitine is one of the cardiotonic components in aconite, with little content. It has a strong effect on the cardiovascular system, and can significantly increase the myocardial contractility of isolated frog heart, eutopic rabbit heart and guinea pig failing heart. After intravenous injection of 1-2 μ g/kg to anesthetized dogs, the maximum rate of left ventricular pressure rise and cardiac output increased, coronary, cerebral, peripheral artery and systemic vascular resistance decreased, myocardial oxygen consumption increased, and the frequency and amplitude of cultured cardiomyocytes in rats also increased. The above effects can be blocked by propranolol, which are similar to the effects of isoproterenol. Norsalsoline in Aconitum carmichaeli is a weak β - stimulant. It can excite the isolated atrium of guinea pigs and increase the frequency of contraction. Intravenous injection can increase the blood pressure and heart rate of normal and spinal cord destroying rats, while spinal cord destroying rats are more sensitive to the pressor effect of norsalsoline than normal rats. Therefore, it is believed that norsalsoline has excitatory effect on both β - receptors and α - receptors. Aconitine in aconite has obvious pressor and cardiotonic effects. Intravenous injection of 40 μ g/kg can increase the blood pressure of rats by 50%, and 3 × 10 (-6) g / ml can increase the contraction amplitude and frequency of isolated guinea pig right atrium by 250 and 120%, respectively. It also has the above effects on cats with spinal cord destruction. Its pressor effect can be abolished by α - adrenergic receptor blocker phentolamine, and its pressor effect and effect on the right atrium of guinea pigs can also be antagonized by ganglion blocker hexahydrocarbon quaternary amine. It is suggested that its effect is related to the excitation of ganglia or preganglionic fibers.
3.2. effect on heart rate and arrhythmia: noraconitine can accelerate heart rate and improve experimental slow arrhythmia. . After intravenous injection, the patient's heart rate increased to varying degrees, sinus bradycardia returned to normal levels, sinus block and node atrioventricular conduction function were improved, so that the conduction block was reduced or disappeared, and the mechanism was mainly to shorten the A-H interval. The experiment also showed that the affinity of noraconitine and isoproterenol for β - adrenergic receptors was similar, but the intrinsic activity was significantly less than that of isoproterenol. Thus it is directly proved that noraconitine is a partial agonist of β - adrenergic receptor. It also has obvious agonistic effect on tracheal β 2-receptor, which is stronger than direct agonistic effect on myocardial B1 receptor. It provides some evidence for the explanation of Fuzi's restoring Yang and rescuing adversity.
The water-soluble part of aconitine (without aconitine alkaloids) 60, 120mg / kg (equivalent to 1 / 10-1 / 5 of the LD50 of mice intravenously) or normal saline (control) was intravenously injected into rats, and aconitine 30 μ g/kg was intravenously injected after 5 minutes of administration. The time of cardiac arrhythmia recorded was significantly delayed than that of the control group (P < 0.001). Six rats in the 120mg / kg group did not show arrhythmia within 20 minutes (P < 0.001). Similar results were also obtained in rats after oral administration of 550 and 1100mg / kg of aconitine water-soluble fraction against aconitine induced arrhythmia. The water-soluble part of Aconitum carmichaeli can significantly convert to normal heart rhythm in rats injected with aconitine 40 μ g/kg and 20 μ g/kg intravenously, 200mg and 400mg / kg intravenously and 500mg and 1000mg / kg duodenally, respectively, after 5 minutes of arrhythmia (P < 0.001). But the water-soluble part of aconite has no effect on ouabain or chloroform induced arrhythmia. It is significant that there are both chemical components that cause and fight arrhythmia in the same crude drug.
. Results it can significantly resist the decrease of aortic pressure (BP), left ventricular systolic pressure (LVP) and the maximum rate of left ventricular pressure rise (LVDP / DT, max), as well as the slowing of heart rate and prolong the survival time. It has a therapeutic effect on endotoxin induced shock. The extract 801 of Aconitum carmichaeli can significantly prolong the survival time of scald shock rats.
3.4. effect on blood flow: aconite has the effect of expanding peripheral blood vessels, Aconite Decoction can significantly expand the blood vessels of the hind limbs of anesthetized dogs and cats, and Aconite Decoction also has this effect. Intravenous injection of 7.5, 15 and 30mg / kg of the water-soluble fraction of aconite could increase the femoral artery blood flow of anesthetized dogs by 30, 70 and 129%, and reduce the resistance by 0.42 and 50%, respectively. The effect could last for about 10 minutes. This effect could explain the warming of limbs after using aconite.
3.5. effect on myocardial ischemia: Fuzi injection and water-soluble part have obvious protective effect on acute myocardial ischemia. The hypoxia tolerance time of mice was significantly prolonged and the alkaline phosphatase activity was decreased. Antagonizing acute myocardial ischemia induced by Pituitrin in rats; It significantly reduced the ST segment elevation of epicardial electrogram in anesthetized dogs caused by ligation of the anterior descending branch and the total number of ST segment elevation.
3.6. other effects: the aqueous extract of aconite can significantly prolong the partial prothrombin time and prothrombin consumption time of the clay. Aconite Qiangxin injection (containing 3mg noraconitine per 1ml) 4ml was added to 400ml 5% glucose injection to maintain intravenous drip in canine acute and chronic disease sinus models, and the sinus node recovery time (snrtc) and epicardial pacing point mapping were measured by intra atrial pacing. The results showed that after aconite injection, the heart rate decreased faster, snrtc shortened, and the pacemaker of the heart also moved, and the vast majority of secondary pacemakers moved up to the sinus node area, providing a basis for clinical treatment of sick sinus. . Aconitum polysaccharide can reduce blood glucose.
4. effect on immune function: observe the effect of Fuzi injection on serum lysozyme activity of mice, blood antibody and spleen antibody cells, and serum complement content of guinea pigs. It is found that Fuzi injection can improve humoral immune function of mice and serum complement content of guinea pigs, but has no obvious effect on serum lysozyme activity of mice; When studying the effect of re garland and cell transformation on cellular immunity, it was found that aconite injection could significantly increase T cells and re garland forming cells. 0.4ml / (kg.d) for 9 days (subcutaneous injection) could significantly increase the lymphocyte transformation rate of rabbits, P < 0.01 compared with the control.
5. mechanism of action on Yang deficiency animal model: cortisone monoamine neurotransmitters in the hypothalamus of Yang Deficiency Rats and normal rats were determined by high performance liquid chromatography with electrochemical detection and camphorsulfonic acid as ion pair reagent. Objective To observe the effect of Fuzi, a Yang supporting drug. The results showed that the norepinephrine (NA) in hypothalamus of cortisone Yang deficiency rats was lower than that of normal rats, and the epinephrine (a) was higher (all P < 0.05). It can return to normal after using aconite. It also increased dopamine (DA) in Keti Songyang deficiency rats and normal rats (P < 0.05 and P < 0.01, respectively), decreased 3,4-dihydroxyphenylacetic acid (DOPAC) (P < 0.001), and increased 5-hydroxytryptamine (5-HT) in normal rats (P < 0.001). After treatment, both Yang deficiency and normal rats showed an increase in DA / DOPAC and 5-HT / 5-hydroxyindoleacetic acid (5-htaa) ratio (P < 0.01-0.001), suggesting that aconite seems to inhibit hypothalamic monoamine oxidase activity.