CN103040946B - Application of lotus nut total alkaloids in preparation of medicament for treating vital myocarditis - Google Patents
Application of lotus nut total alkaloids in preparation of medicament for treating vital myocarditis Download PDFInfo
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- CN103040946B CN103040946B CN2013100355184A CN201310035518A CN103040946B CN 103040946 B CN103040946 B CN 103040946B CN 2013100355184 A CN2013100355184 A CN 2013100355184A CN 201310035518 A CN201310035518 A CN 201310035518A CN 103040946 B CN103040946 B CN 103040946B
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Landscapes
- Medicinal Preparation (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention provides application of lotus nut total alkaloids in preparation of a medicament for treating vital myocarditis. The medicament for treating the vital myocarditis provided by the invention has good efficacy on an acute stage and a chronic stage, and a traditional Chinese medicine is consolidated and lasting in efficacy, low in toxic and side effects and cheap in price.
Description
Technical field
The present invention relates to the new purposes of Plumula Nelumbinis total alkaloids.Belong to drug world.
Background technology
Viral myocarditis refer to by Coxsackie virus, dust can (ECHO), poliomyelitis, the influenza infection myocardium limitation or the diffuse acute or chronic inflammatory disease pathological changes that cause, belong to infectious cardiomyopathy.Account for 40% by the Coxsackie virus infection causer.Other virus has: dust can (ECHO), poliomyelitis, influenza, parainfluenza virus, measles, parotitis, encephalitis B, hepatitis virus, varicella zoster virus, cytomegalovirus, HIV (human immunodeficiency virus), infectious monocytosis etc.Virus function is directly to invade little blood vessel injury in cardiac muscle and cardiac muscle in myocardium mode.Produce cardiac damage by immunologic mechanism plays an important role in myocarditic morbidity.The direct infringement of virus and immunoreation mediation cause the myocardial cell infringement, make heart systolic and diastolic function obstacle; If pathological changes is involved pace-making or the conducting systems such as sinuatrial node, atrioventricular node, bundle branch, can cause various types of arrhythmia.Clinical main manifestations often first has the symptoms such as heating, systemic pain, pharyngalgia, asthenia, nausea,vomiting,diarrhea for patient, cardiopalmus, uncomfortable in chest, chest pain or pareordia dull pain, dizziness, dyspnea, edema, even Adams-Stokes syndrome then occur; Heart failure or cardiogenic shock appear in only a few patient.
The Plumula Nelumbinis source is dry spire and radicle in the mature seed of nymphaeaceae plant lotus (Nelumbo nucifera Gaertn.).Fujian, main product ground, Hunan etc.The Plumula Nelumbinis chemical composition mainly contains: outside liensinine, isoliensinine, (-)-Neferine, also containing nuciferine, pronuciferine (+)-Pronuciferine and water-soluble alkaloid C19H23NO3, S-N-methyl coclaurine (S-N-methyIisococlaurine) and dl-armepavine (dl-armepavine).Except containing alkaloid, also contain flavones ingredient: the compounds such as rutin, hyperin, luteolin in Plumula Nelumbinis; Obtain 7 compounds such as Palmic acid, cupreol, cupreol-3-o-β-D-Glucose glycoside, cupreol normal octane acid esters and cupreol Palmic acid from the puny polar components separation of Plumula Nelumbinis again in recent years.Wherein cupreol normal octane acid esters and cupreol Palmic acid system get first in this plant.Separate and obtain multiple volatile oil component from the Plumula Nelumbinis plumule: hyaluronic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, linoleic acid, stearic acid, arachidic acid, heneicosanoic acid, behenic acid, lignoceric acid, Squalene etc.Also contain in addition the trace element such as chlorophyll, water soluble polysaccharide and zinc, copper, ferrum, calcium, magnesium sodium, potassium, nickel, manganese, cadmium in Plumula Nelumbinis.The Plumula Nelumbinis total alkaloids document of report is more at present, as: Liu Wei, Deng, the preparation technology of Plumula nelumbinis Alkaloid drop pill and assay, CHINA JOURNAL OF CHINESE MATERIA MEDICA, April in 2007, the 32nd the 7th phase of volume, reported that the Plumula nelumbinis Alkaloid main component is 3 kinds of bisbenzylisoquinoline alkaloids such as (-)-Neferine, isoliensinine and liensinine, can be used for the arrhythmia symptom that treatment is caused by the multiple heart disease such as myocardial ischemia, coronary heart disease.Li Juan, etc., processes of alkaloids from Lotus plumule health care progress, grain and oils and fats, the 1st phase in 2010, reported that processes of alkaloids from Lotus plumule has the multiple medicinal and health cares such as blood pressure lowering, antioxidation, protection cardiac muscle.
Summary of the invention
Technical scheme of the present invention has been to provide the total biological new purposes of Plumula Nelumbinis.
The invention provides the purposes of Plumula Nelumbinis total alkaloids in the medicine of preparation treatment viral myocarditis.
The present invention also provides the purposes of Plumula Nelumbinis total alkaloids in the medicine of the anti-Coxsackie virus of preparation.Wherein, described Coxsackie virus is Coxsackie B virus.Further preferably, described Coxsackie virus is Coxsackie B virus 3m.
Wherein, described Plumula Nelumbinis total alkaloids derives from dry spire and radicle in the mature seed of nymphaeaceae plant lotus (Nelumbo nucifera Gaertn.).
Wherein, in described Plumula Nelumbinis total alkaloids the weight percentage of total alkaloids more than 70%.
Wherein, described medicine is to take the Plumula Nelumbinis total alkaloids as active component, the preparation that adds pharmaceutically acceptable adjuvant or complementary composition to be prepared from.
Wherein, described preparation is tablet, capsule, granule, drop pill.
Wherein, in described drop pill, the weight percentage of (-)-Neferine is not less than 40%, and the weight percentage of isoliensinine is not less than 12%, and the weight percentage of liensinine is lower than 12%.
Medicine of the present invention is used for the treatment of viral myocarditis, no matter be acute stage or chronic phase curative effect preferably all to be arranged, and the effective in cure consolidation of Chinese medicine, lasting, toxic and side effects is less, low price.
The specific embodiment
The extraction process of embodiment 1 Plumula Nelumbinis total alkaloids of the present invention
Plumula Nelumbinis 2kg, with 80% ethanol (8 times of amounts) merceration 12h, stir and extract 3 times with electric blender after pulverizing, each 2h.Merge ethanol, decompression and solvent recovery is to proper volume, sucking filtration.Filtrate is adjusted pH to 2-3 with 1% hydrochloric acid, filters, and filtrate is adjusted pH to 9-10 with ammonia again, and for several times, combined chloroform liquid, boil off solvent to chloroform extraction, and drying under reduced pressure 24h obtains yellow solid total alkali 20g to constant weight.Obtain the Plumula Nelumbinis total alkaloids.
The extraction of embodiment 2 Plumula Nelumbinis total alkaloids of the present invention
The Plumula Nelumbinis medical material, pulverize, and adding 0.2%HCL/30% ethanol is solvent, and 6 times of quantity of solvent are extracted 3 times, each 1h.Select D101-A purification with macroreticular resin Plumula nelumbinis Alkaloid, after first with distilled water, 4 times of resin volumes of 15% ethanol elution, removing water-solubility impurity, with 4 times of resin volume enrichment total alkaloidss of 70% ethanol elution, the pressure reducing and steaming solvent, be dried to constant weight.The total alkali extracting solution of Plumula Nelumbinis is after purification by macroporous resin is processed, and refined yield is the highest, and total alkaloid content obtains the Plumula Nelumbinis total alkaloids more than 70%.
The preparation of embodiment 3 Plumula Nelumbinis total alkaloids of the present invention drop pill
Plumula Nelumbinis total alkaloids extract (embodiment 1 or embodiment 2 preparations) is 1:5 with containing 70%PEG4000 substrate ratio, 85 ℃ of fluid temperature, and liquid coolant is dimethicone, 10 ℃ of chilling temperatures, cooling column length is 80cm, drips apart from 3.5cm, drips 25/min of speed.The application high effective liquid chromatography for measuring, the (-)-Neferine average content must not be lower than 40%, and the isoliensinine average content must not be lower than 12%, and the liensinine average content must not be lower than 12%.
This preparation can be tablet, capsule, and soft capsule (soft gelatin capsule), the pharmacy such as pill can be for the form of administration.
Except the Plumula Nelumbinis total alkaloids of embodiment 1 and embodiment 2 preparations, also comprise Plumula Nelumbinis total alkaloids prepared by the method that adopts current bibliographical information.
Below prove beneficial effect of the present invention by concrete clinical trial and pharmacodynamics test.
Test example 1 medicine therapeutic virus myocarditis of the present invention clinical observation on the therapeutic effect
1 data and method
1.1 clinical data is chosen in the attached the People's Hospital of Fujian university of TCM viral myocarditis (VMC) patient 60 examples of being in hospital, male 27 examples, female's 33 examples, year at age 8～39 (21.3 ± 3.5), 1 month～2.5a of the course of disease, average 0.55a.All meet the VMC diagnostic criteria of national myocarditis cardiomyopathy symposium in 1999 revision, sick acute viral infection history, main clinical manifestation are arranged in first 1～3 week is heating, cardiopalmus, pain uncomfortable in chest, breathe hard, weak and arrhythmia; Electrocardio diagram sinus tachycardia, non-specific multipole and intraventricular block; Ultrasonic cardiography diagram cardiac dilatation and myocardium shrinkage function are incomplete; Myocardial enzymes increases, and cardiac muscle biopsy has the characteristic inflammation to change.With reference to " new Chinese medicine treatment viral myocarditis guideline of clinical investigations " standard diagnostics, be VMC, and the heresy that meets differential diagnosis in tcm feel frustrated the moon, deficiency of both QI and YIN, deficiency of both YIN and YANG syndrome.Get rid of hyperthyroidism, beta receptor hyperfunctioning and other heart diseases, gestation and women breast-feeding their children, have drug allergy history or allergic constitution person.The patient is divided into to treatment group, each 30 examples of matched group at random, and two groups of clinical datas have comparability.
1.2 quiet polarized solution of Therapeutic Method matched group (10% Glucose Liquid 500ml+ insulin 8U+10% potassium chloride 10m1), 1 time/d; Oral ubiquinone
1010mg, vitamin C 0.2g, 3 times/d; Take the circumstances into consideration to use general anti-arrhythmic, be 4 weeks the course for the treatment of.Treatment group oral drugs group (embodiment 3) 4 tablets/times, 4 times/d; Take the circumstances into consideration to use general anti-arrhythmic, be 4 weeks the course for the treatment of.During treatment, observe two groups of clinical manifestations, 24h ambulatory electrocardiogram, Myocardial Enzymologic and changes of cardiac function.Criterion of therapeutical effect with reference to " new Chinese medicine treatment viral myocarditis guideline of clinical investigations " is judged curative effect.
1.3 detection method is the 24h dynamic ecg recordings examination 1.: adopt Holter to detect two groups of 24h ambulatory electrocardiograms.2. Myocardial Enzymologic detects: adopt automatic clinical chemistry analyzer to detect two groups of lactic acid dehydrogenases (LDH) and creatine kinase isozyme (CK.MB).3. antiviral antibody detects: adopt ELISA method, IgM enzyme-linked immunologic detecting kit to detect two groups of Coxsackie B virus antibody.4. cardiac function detects: adopt color doppler ultrasonography two groups of left cardiac ejection fractions of detection aroused in interest (LVEF) and cardiac index (CI).
1.4 statistical method adopts the SPSS11.0 statistical software, data are used
mean, measurement data is relatively with the t check, and enumeration data is relatively with check.There is statistical significance P≤0.05 for difference.
2 results
28 examples 2.1 the clinical efficacy treatment group is clearly better or takes a turn for the better, invalid 2 examples, effective percentage 93.3%; Matched group is respectively 20,10 examples, effective percentage 66.7%.The treatment group effective percentage obviously is better than matched group (P<0.05).
2.224h the premature beat of ambulatory electrocardiogram performance treatment group takes a turn for the better or recovers 14 examples, ST-T changes recovery 11 examples, and atrioventricular block improves 8 examples; Matched group is respectively 7,4,5 examples.Two groups more all have significant difference (P<0.05 or<0.01).
The situation 2.3 lab testing is turned out cloudy, coxsackie B antibody positive 23 examples before the treatment group treatment, 19 examples of turning out cloudy after treatment; Matched group is respectively 21, the l0 example.Two groups relatively have significant difference (P<0.05).Before and after two groups of treatments, myocardium enzyme changes in Table 1.
Myocardium enzyme variation before and after table 1 liang group treatment (U/L,
)
Annotate: with comparison after treatment of control group, * P<0.05, * * P<0.01.
2.4 before and after the treatment of changes of cardiac function treatment group, LVEF, CI are respectively (43.97 ± 6.95) %, 2.5 ± 0.8, (57.98 ± 6.81) %, 3.5 ± 0.7; Matched group is respectively (44.15 ± 5.84) %, 2.6 ± 0.8, (53.11 ± 8.15) %, 3.2 ± 0.5.More equal no difference of science of statistics before two groups of treatments (P is equal > 0.05), significant difference (P<0.05) is more all arranged after treatment.
Test example 2 medicine of the present invention infects Balb/c mouse core myositis therapeutical effect to Coxsackie B virus 3m
Material
1. the male Balb/c mice of the clean level of animal is 240,4-6 age in week, weight (14 ± 2) g.
2. viral CVB3m(Nancy strain), by U.S. ATCC, introduced.
3. instrument computer image analysis instrument (three-hypers CMISA series is developed jointly by Beijing Aviation university picture centre and Beijing Zhong Shan Bioisystech Co., Ltd); CO2 incubator (U.S. Nuaire-4950E); Microplate reader (Bio-RAD, Bench mark); Inverted microscope (German LECIA); Ultra cold storage freezer (MDF382E, Japanese SONY).
4. reagent D MEM(Dulbecco ' s Modified Eagle Media) purchased from U.S. Gibco company; Hyclone (TBD0032HYP), purchased from U.S. Gibco company.
Method
1. medicine prepares above-mentioned Plumula Nelumbinis total alkaloids (embodiment 2).
2. grouping is divided into 6 groups with modeling at random by 288 Balb/c mices, i.e. the high, normal, basic Three doses group of medicine group, positive group, the model group of viral myocarditis and Normal group.Every group is 48.The CVB3m virus liquid of the equal lumbar injection 0.1mL of model group and medication therapy groups 50tissue infection dose (tissue culture infective dose, TCID50), normal group is given equivalent not containing viral culture fluid lumbar injection.
3. administration modeling while treatment group is pressed (in primary crude drug 10g Plumula Nelumbinis medical material/kg) and is given the medicine gavage, and positive group dosage is the 50mg/kg(virazole); Model group and normal group give respectively equivalent distilled water gavage, continuously gavage 14d.
4. experimental index
4.1 observe fur, stool, the mental status that mice is respectively organized in general state observation every day, the periodic measurement weight.
4.2 calculate survival rate mice 14d survival rate=respectively organize survival mice number/respectively organize total mice * 100%.
Every group of the modeling the 3rd, 5,7,10 4.3 draw materials, 14d are got 6 at random, weigh; Core dirty, suck residual blood and the tissue fluid of heart tissue with filter paper, carry out precise weighing, calculate heart/weight (%)=cardiac mass (g)/weight (g) * 100%.Along the left ventricle axle, vertically cut, the heart right-hand part is put into the EP pipe, is placed in rapidly curling stone and saves backup; Remainder is fixed for histopathology with 4% paraformaldehyde and detects.
4.4 the CVB3m of cardiac muscular tissue virus titer is measured the dirty right half part of coring and shredded with eye scissors, grinds, 4 ℃ of centrifugal 10min of 2000r/min, get supernatant, with protein-nucleic acid analysis-e/or determining protein concentration, gets 0.2mL from 10
-1to 10
-8doubling dilution, be inoculated on the Microtitration plates that grows up to monolayer Hela cell, cultivates 48h for 37 ℃, and the observation of cell pathological changes adopts the Reed-Muench method to measure the TCID50 of virus in cardiac muscular tissue, the virus titer of calculating myocardium homogenate.
4.5 myocardium pathology histology is made pathological section by cardiac muscular tissue, puts micro-Microscopic observation.Adopt image analysis system, the thought-read flesh gross area and the pathological changes gross area and focus sum, calculate the pathology integration=pathological changes gross area/institute thought-read flesh gross area * 100 respectively.
5 serum cardiac enzymatic determinations
Each is organized mice and plucks eyeball and get blood, shake up gently, in 4 ℃, the centrifugal 10min of 3000r/min, separated plasma, measure the content of aspartate transaminase (AST), lactic acid dehydrogenase (LDH), creatine kinase (CK), creatine kinase isozyme (CK-MB) etc. in serum by microplate reader, operate according to the test kit description.
6. statistical method adopts SPSS11.5 medical statistics software to be analyzed, measurement data with
mean, the measurement data of 3 groups adopts monofactorial variance analysis, relatively adopts in twos the LSD analytical method.
The rate analysis of enumeration data adopts χ
2check.
Result
1. the model group 3d mice activity that affects of mice general state reduced, appetite reduces, the fur filth, and diarrhoea appears in the part mice.5-7d mice lethargy, move curling oneself up less, and weight obviously alleviates, and dead mouse is counted showed increased.10-14d survival mice state takes a turn for the better gradually, and goodbye does not have dead mouse.Each administration group mice fur, activity, diet situation obviously are better than model group.
On the impact of Mice Body quality in Table 2.Before modeling, each organizes Mice Body quality there was no significant difference.After model group mouse infection virus, weight presents downward trend; Descending in various degree also appears in each treatment group weight after infection, but fall is lower than model group (P<0.05), but low dose group is compared without significance with model group.Between 3 groups, the weight difference of each time point is not remarkable.
Table 2 respectively organize Mice Body mass change situation (
n=6, g)
Annotate: compare * P<0.05, * * P<0.01 with model group.
On the impact of mouse survival rate in Table 3.The mouse survival number of 3 various dose administration groups is obviously more than model group.The survival rate of 14d model group is 68.75%, and high dose group is 87.5%, and middle dosage group is 89.58%, and the percentage survival that low dose group is 79.17%, 3 treatment group, all higher than model group, has significant difference (P<0.05=; Survival rate difference between 3 groups is not remarkable.
Table 3 is respectively organized survival rate (n=48, %) in mice 14d
Annotate: compare * P<0.05, * * P<0.01 with model group.
On the impact of mouse cardiac muscle inner virus titre in Table 4.3 dosage group medicines at metainfective virus titer obviously all in various degree lower than viral group (P<0.05, P<0.01).
Each 3 groups of mouse cardiac muscle inner virus titres comparisons (LogTCID50) of table 4 (
n=6)
Annotate: compare * P<0.05, * * P<0.01 with model group;
On the impact of mouse heart quality in Table 5.The cardiac mass of model group/weight ratio and normal group significantly increase (P<0.01).The ratio of the cardiac mass/weight of 3 treatment groups is compared with model group, extremely significantly reduces (P<0.01), and the ratio difference of the cardiac mass/weight between 3 treatment groups is significantly (P>0.05) not
Table 5 respectively organize the mouse heart quality (
n=30)
Annotate: compare * P<0.05, * * P<0.01 with model group.
On the impact of mouse cardiac muscle pathological change in Table 6.Normal group myocardial cell marshalling, without inflammatory cell infiltration.The visible myocardial cell swelling of virus model group, inflammatory cell infiltration, serious visible extent of disease increases, or is the distribution of many kitchen ranges, myocardium cell necrosis occurs, very can involve visceral pericardium.The myocardium pathology integration of 3 treatment groups is significantly lower than model group (P<0.05, P<0.01).Middle dosage group and high dose group pathological changes ratio are significantly lower than low dose group (P<0.05).
Table 6 respectively organize mouse cardiac muscle pathology integral contrast (
n=30)
Annotate: compare * P<0.05, * * P<0.01 with model group;
7., after serum cardiac enzymatic determination result infects virus, in mice serum, AST, CK, LDH, CK-MB content all raise.With the M group, compare, the These parameters of each administration group is active obviously to descend.The order of curative effect from excellent to inferior that shows various medicines from the testing result of twice is: SM>SH>the SL group, wherein SM, SH group reduces LDH, CK, the CK-MB level is evident in efficacy, with the more variant P<0.05(of M group in Table 7) table 7 Plumula Nelumbinis extract is on the impact (n=10 of myocarditis serum cardiac enzyme, U/L
)
Annotate: compare * P<0.05, * * P<0.01 with normal group.
In sum, by clinical trial, prove, medicine of the present invention is used for the treatment of viral myocarditis (VMC), and drug effect is obvious, and effective percentage reaches 93.3%; By animal experiment, prove, medicine of the present invention can improve the mouse survival rate, and cardiac mass infects Balb/c mouse core myositis therapeutic effect to Coxsackie B virus 3m remarkable, for clinical, provides a kind of new medication to select.
Claims (9)
1. the purposes of Plumula Nelumbinis total alkaloids in the medicine of preparation treatment viral myocarditis.
The Plumula Nelumbinis total alkaloids the preparation anti-Coxsackie virus medicine in purposes.
3. purposes according to claim 2, it is characterized in that: described Coxsackie virus is Coxsackie B virus.
4. purposes according to claim 3, it is characterized in that: described Coxsackie virus is Coxsackie B virus 3m.
5. according to the described purposes of claim 1-3 any one, it is characterized in that: described Plumula Nelumbinis total alkaloids derives from dry spire and radicle in the mature seed of nymphaeaceae plant lotus Nelumbo nucifera Gaertn..
6. purposes according to claim 5, it is characterized in that: in described Plumula Nelumbinis total alkaloids, the weight percentage of total alkaloids is more than 70%.
7. according to the described purposes of claim 1-4 any one, it is characterized in that: described medicine is to take the Plumula Nelumbinis total alkaloids as active component, the preparation that adds pharmaceutically acceptable adjuvant or complementary composition to be prepared from.
8. purposes according to claim 7, it is characterized in that: described preparation is tablet, capsule, granule, drop pill.
9. purposes according to claim 8, it is characterized in that: in described drop pill, the weight percentage of (-)-Neferine is not less than 40%, and the weight percentage of isoliensinine is not less than 12%, and the weight percentage of liensinine is lower than 12%.
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