CN101799462A - Method for quantitative evaluation of drug effect by applying metabonomic technology - Google Patents
Method for quantitative evaluation of drug effect by applying metabonomic technology Download PDFInfo
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Abstract
The invention discloses a method for quantitative evaluation of drug effect by applying the metabonomic technology. The method is characterized by comprising the following steps: measuring small-molecule compounds in a biological sample in an overall and quantified manner by using the metabonomic method based on mass spectrometry, nuclear magnetic resonance and other measurement technologies; and further establishing a multi-dimensional space mathematical model by using the multi-variable data processing method, to calculate the relative distance between an administration group and a control group as the quantified index for evaluating the drug effect, thus solving the difficult problem that the quantified evaluation index is not available to the evaluation for the drug effect of various drugs. Compared with the conventional method for evaluating the drug effect, the method of the invention has the advantages of wide applicable range, high sensitivity and convenient sampling process, prevents organisms from being harmed and embodies the drug effect in an overall and integrated way, thus providing an overall and reliable quantified evaluation method for evaluating drug effect for the development of new drugs and the research on pharmacology.
Description
Technical field
The present invention relates to the new method of drug effect quantitative evaluation, be specifically related to adopt endogenous micromolecular compound in gas chromatography detection by quantitative people, animal or the cell, adopt multivariate data disposal route computational mathematics model, calculating administration group and control group relative distance method as the drug effect quantitative evaluation.
Background technology
For a long time, in pharmacological research, the drug effect of many medicines relies on qualitative and non-quantitation, subjectivity but not objective, rough but not accurate, unilateral but not comprehensive standard are estimated, and the concrete deficiency of these methods is mainly reflected in:
1.
Quantizating index lacksThough evaluating drug effect has adopted some convenient, effectively evaluating indexs, as body weight, blood pressure, blood sugar, transaminase, blood platelet, cell number etc., but the drug effect that also has many medicines lacks clear and definite quantizating index, is difficult to carry out accurate detection and evaluation with existing method.The for example power of degree of fatigue, pain degree and analgesic effect, body rejection and the effect of immunodepressant, excited, anxiety or act on the drug effect of spirit, neurological drug, myocardial contractive power or gastrointestinal movement are to strengthen or weaken; Blood vessel or bronchus are expansion or contraction etc.
2.
SubjectivityFor want of objective quantitative target, the evaluation of many drug effects can only be taked subjective artificial evaluation or qualitative, have to rely on quilitative method (as histotomy, imaging technique, various electron microscopic examinations etc.) or experience judgement or subjective sensation to carry out scalar quantization to the evaluation of these drug effects, make drug effect pass judgment on and have very big subjectivity and uncertainty.
3.
One-sidednessThere is certain one-sidedness in many indexs, have just reflected the state of indivedual biochemical functions, organ-/ tissue, lack evaluation criterion whole, system.As indexs such as transaminase, kreatinin, erythrocyte sedimentation rates.
4.
NocuitySome evaluation methods are big or expense is expensive to body injury, as biopsy, intervention, radiography, tomoscan etc., lack damaging little, economy method easily.
In a word, the method limitation of existing many evaluating drug effects is bigger, lack quantitative criterion, lack objectivity, comprehensive, specific aim and novelty, be unfavorable for drug effect is carried out quantitative, objective and accurate evaluation, become the great difficult problem of the huge obstacle and the puzzlement pharmaceutical research of serious restriction pharmaceutical research.Need research badly and found convenient, reasonable, widely used new method of evaluating drug effect.
Body endogenous small-molecule substance group is the basis of vital movement, and the functional status of body must be reflected on the internal metabolism group (endogenous micromolecular compound general name).Studies show that, obviously unusual at morbid state lower body metabolic function and a lot of micromolecular compound level.And in drug therapy and body rehabilitation course, along with every function of body is recovered gradually, micromolecule and metaboilic level is also adjusted gradually or correct in the body.And have significant correlativity between a little less than the adjusting of metabolism group or degree that lapses to and the strong drug action, promptly drug effect is strong more, good more, micromolecule level also approaching more normal (away from morbid state) in every functional status/body of body; Drug effect is weak more, poor more, and the micromolecule level is also the closer to morbid state (away from normal condition) in every functional status/body of body.
Utilize suitable metabolism group testing tool, hundreds of even thousands of molecular weight are less than 1000 all kinds of micromolecular compounds in can the detection of biological sample.Be determined as example with GC/TOFMS, to a lot of compound test sensitivity up to 10
-12Mol (absolute sense limit), relative sensitivity reaches 10
-9Mol/mL.These compounds comprise nearly all amino acid, glycitols compound, fatty acid, lipid, small molecular organic acid class, nucleosides and purine compound, ammoniac compounds, neurotransmitter or the like, they are the essential raw material of vital movement, also be organism metabolism product/intermediate, or the important substance basis of body growth, growth, bio signal conduction and metabolic cycles.Closely related with the glycometabolism that plays vital role very in the vital movement, lipid metabolism, tricarboxylic acid cycle, urea cycle, amino acid circulation etc.Therefore, micromolecular variation both can embody to system synthesis the result of drug action in the body of detection, can also be according to sample displacement quantitative evaluation drug effect before and after the administration.Up to now, also do not utilize the metabolism group data to set up mathematical model, calculating administration group and control group relative distance are carried out quantitative evaluation to drug effect report.
Summary of the invention
Technical matters to be solved by this invention is: utilize the metabolism group method, endogenous micromolecule in the quantitative measurement biological specimen comprehensively,, the The data multivariate data disposal route that obtains is set up mathematical model, calculate the relative distance of administration group and control group, with the index of this quantitative value, solve the problem that many drug effects lack accurate method for quantitatively evaluating as evaluating drug effect.
For addressing the above problem, the invention provides following technical scheme, step comprises:
Sample collecting and processing: gather all kinds of biological specimens such as clinical patient, animal pattern, tissue/cell, be generally the cell or the nutrient solution of blood, urine, in vitro culture; Sample carries out liquid-liquid through organic solvent and extracts, and organic solvent comprises ethyl acetate, chloroform, ether, normal butyl alcohol, sherwood oil, methylene chloride, acetonitrile; Or through albumen precipitation, the method for albumen precipitation comprises that the independent or comprehensive modes of method such as adding organic solvent (as methyl alcohol, ethanol, acetone, acetonitrile, isopropyl alcohol), various soda acid salt precipitation, thermal precipitation, filtration/ultrafiltration, Solid-Phase Extraction handle; Sample can not carry out drying, or first drying is utilized all kinds of solvent dissolvings that contain organic solvent and water (saliferous or not saliferous separately or comprehensive) again; Sample does not carry out derivatization or utilizes reagent to carry out derivatization treatment.
Sample analysis and data processing: adopt based on mass spectroscopy and chromatograph joint used technical method or the assay method of nuclear magnetic resonance technique above-mentioned sample is detected, these methods can be liquid chromatography-mass spectrography, gas chromatography-mass spectrum, Capillary Electrophoresis chromatography-mass spectroscopy, nuclear magnetic resonance etc.; Through obtaining the quantitative data at each peak in the chromatogram after the data processing, these data can be peak area or peak height, or the quantitative data that is calculated by peak area or peak height.
An outstanding advantage of the present invention be above-mentioned detection method can detection bodies in a large amount of micromolecular compounds, and thoroughly evaluating drug effect effect/or the health status of body based on this.When drug action was strong, whole metabolism spectrum was near normal, and drug effect is when more weak, and the metabolism spectrum changes not obvious.The GC/TOF-MS that Fig. 1 has provided Hypertensive Rats (SHR) and normal rat (WKY) (serum sample) measures total ions chromatogram, from chromatogram as can be seen, the total ion current of two kinds of rats is strivied for survival in difference, but the method for this visual observations can only be done rough, a subjective judgement, can't realize quantitative evaluation.
The calculating of mathematical model foundation and relative distance value: the various multivariate data process softwares of above-mentioned The data, can be SPSS, Matlab, SIMCA-P etc., select partial least square method-discriminatory analysis (PLS-DA), quadrature partial least square method (OPLS), quadrature partial least square method-discriminatory analysis (OPLS-DA), principal component analysis (PCA) (PCA), Nonlinear Mapping (Nonlinemapping, NLM), cluster analysis methods such as (HCA) is set up mathematical model, obtain model parameter and the sample volume coordinate in the multidimensional mathematical model, calculate administration group sample and control group relative distance.The hyperspace here can be 1,2,3 dimensions, also can be 4,5,6 even hyperspace more.Above-mentioned control group can be an own control before the administration, also can be the model group parallel control of not administration, can also be the normal group contrast of not administration.Above-mentioned space relative distance can be got the coordinate mean value of respectively organizing sample earlier, calculates again, also can calculate distance between each sample earlier, and averaging obtains again.
The outstanding advantage that adopts the method for principal component analysis (PCA) (PCA), partial least square method-discriminatory analysis Projection Analysis such as (PLS-DA) is to observe the relative position of each sample in the hyperspace model convenient, intuitively, Fig. 2 shows that the general ginsenoside administration can regulate unusual metabolism state in hypertension model rat (SHR) body, make it to level off to gradually normal rat (WKY), embody adjusting and the correction effect of medicine Hypertensive Rats metabolism group.
The same with above-mentioned total ion current figure, though the method for visualization is used for the qualitative judge of drug effect in a large number like this, its subject matter is to quantize, and the result judges and has subjectivity.
Beneficial effect of the present invention:
Because morbid state lower body metabolic function and micromolecule level are unusual, the performance on metabolism group is exactly away from normal group.Through drug therapy, body is rehabilitation gradually, metabolism group show as near normal, away from disease; Drug effect is strong more, approaching more normal, away from disease; Drug effect weak more then away from normal, near disease.
1. utilize the metabolism group result of study can quantitative response medicine effect, strengthened objectivity and accuracy, avoided some pharmacodynamics indexs can only adopt the problem of artificial and subjective judgement.
2. utilize the metabolism group result of study can synthetically reflect medicine effect comprehensively, avoided some pharmacodynamics indexs only to reflect the problem of local drug effect.
3. the quantizating index of metabolism group is widely applicable, applicable to the quantitative evaluation of all kinds of disease drug effects.
4. the method for evaluating drug effect of metabolism group adopts blood plasma, urine equal samples, and cost is low, little to the body injury.
Description of drawings
Fig. 1 GC/TOF-MS measures the total ions chromatogram of Hypertensive Rats (SHR) and normal rat (WKY), from chromatogram as can be seen, the total ion current of two kinds of rats is strivied for survival in difference, but the method for this visual observations can only be done rough, a subjective judgement, can't realize quantitative evaluation.
Fig. 2 general ginsenoside administration group, hypertension control group and normal control group are at 0,2,4,6,8 all sample distribution scatter diagrams.General ginsenoside not only demonstrates tangible hypotensive effect to Hypertensive Rats, and through 8 all administrations, can regulate unusual metabolism state in hypertension model rat (SHR) body, level off to normal rat (WKY) gradually, on directly perceived as can be seen medicine to the adjusting and the correction effect of Hypertensive Rats metabolism group.The same with above-mentioned total ion current figure, though the method for visualization is used for the qualitative judge of drug effect in a large number like this, its subject matter is to quantize, and the result judges and has subjectivity.
Embodiment
The present invention carries out detailed explanation by the following examples, but and does not mean that the present invention only limits to this.
Embodiment
General ginsenoside is to the regulating action of Hypertensive Rats metabolism group
1. experimental program and sample collecting
8 all spontaneous hypertensive rat in age (SHR) adaptability raised for two weeks, since giving general ginsenoside 30mg/kg/d (i.p) the 10th week, to 18 weeks stopping administration, continued to measure blood pressures after the drug withdrawal in 2 weeks.Other one group of SHR rat and normal rat (WKY) are given and are given physiological saline as model contrast and normal control.Tail cover method is surveyed and is respectively organized blood pressure weekly, and per two weeks take a blood sample once, each 0.3ml, blood leaves standstill 1h 37 ℃ of water-baths, and 3500rpm is centrifugal, and upper serum ,-80 ℃ of preservations are collected in the back, a part is used for the serum biochemistry analysis, and another part is used for the mensuration of metabolism group, and the rat fasting is 12 hours before the blood sampling.
The result: blood pressure measurement shows that normal WKY rat blood pressure in experimental session keeps steadily normal, hypertension SHR rat blood pressure is significantly higher than normal rat (p＜0.01), and have and continue slow rising trend, and general ginsenoside administration group blood pressure gradual slow descends, even drug withdrawal 2 all blood pressures still maintain reduced levels, demonstrate lasting hypotensive effect.General ginsenoside administration group, hypertension control group and the blood pressure determination of normal control group the results are shown in Table 1.
2. sample preparation
Freezing serum is at 37 ℃ of water-baths 20min that thaws, and after the vortex vibration, gets 50 μ l and adds 200 μ l and contain stable isotope
13The methanol solution (12.5 μ g/ml) of the interior mark meat bandit acid of C, vortex vibration 3min, 4 ℃ of refrigerators left standstill 1 hour, and 19600g and 4 ℃ of centrifugal 10min get 100 μ l supernatants in the GC bottle, and decompression volatilizes.Add 30 μ l methoxamine pyridine solutions (10mg/ml) in the GC bottle, vortex vibration 3min leaves standstill 16h and carries out oximate under the room temperature.Add 30 μ l TMS trifluoroacetyl MSTFA (containing 1%TMCS) as catalyzer, vortex vibration 1min, room temperature leaves standstill 1h and carries out derivative reaction, adds the n-heptane solution (30 μ g/ml) of 30 μ l external standard methyl meat bandit acid esters at last again, carries out GC-TOF/MS after the mixing and detects.
3.GC/TOF-MS measure
Instrument: (GC:Angilent 6890N gas chromatograph is equipped with Angilent 7683B automatic sampler and 100 sample feeding dishes of G2614A type to gas chromatography-flight time mass spectrum (GC/TOF-MS) detection system; TOF-MS:Pegasus III, Leco, USA).
Chromatographic condition: chromatographic column is DB-5 quartz capillary column (10m * 0.18mm i.d., J﹠amp; W Scientific, USA), sample size: 1 μ l, adopt the original mold formula that flows to that is regardless of; Carrier gas: helium; Constant current speed: 1ml/min; The temperature programme pattern: 70 ℃ keep 2.0min, with 35 ℃/min linearity linear temperature increase to 305 ℃ at the uniform velocity, keep 2.0min then.
Mass spectrum condition: injector temperature: 250 ℃; Scavenging period and flow velocity: 1min, 20ml/min; Transfer tube temperature: 250 ℃; Ion source temperature: 200 ℃; Ion gun voltage and current :-70eV, 3.0mA; MS adopts the full scan mode to carry out data acquisition, and MS adopts the full scan mode to carry out data acquisition; Sweep limit: m/z 50-800; Sweep velocity: 20spectra/s; Detecting voltage is-1690v.
Measurement result: the GC/TOF-MS total ions chromatogram (Fig. 1) that under above-mentioned testing conditions, can obtain sample.The software (ChromaTOF 2.00) that utilizes instrument to carry can extract each chromatographic peak peak area in each working sample chromatogram, form a data matrix of forming by peak area, this data matrix comprises general ginsenoside administration group, hypertension model group and normal group totally 84 samples (being first row) and 154 chromatographic peaks (being first row), is kept in the excel file.
4. the calculating of mathematical model foundation and relative distance value
With above-mentioned data call in multivariate data analysis soft sim CA P-11 (Umetrics AB,
Sweden) in, utilize data internal relation projection-offset minimum binary-discriminatory analysis (PLS-DA) computational mathematics model, the major component number of determining model is 2, this mathematical model is one 2 dimension space model, each sample all is a point in this space, and its position is determined by x and y coordinate parameters.Can obtain the distribution plan of each sample in the planimetric coordinates of this model, Fig. 2 by above-mentioned model.
Extract the volume coordinate parameter of each sample in model, calculate the mean value of every group of sample x and y coordinate according to following formula (1), again the hypertension of calculating administration group and not administration according to formula (2), (3) contrast and the normal control group of not administration between distance.In addition, according to formula (4) can calculate the administration group and the same period hypertension model group and the relative ratio of normal group distance, the expression medication to the regulating degree of Hypertensive Rats internal metabolism group/be strong drug action a little less than.
Formula 1:
Xi＝(Xi1+Xi2+Xi3+Xi4+Xi5+Xi6)/6
Yi＝(Yi1+Yi2+Yi3+Yi4+Yi5+Yi6)/6
Xi, Yi are respectively administration group i week horizontal ordinate and ordinate mean value.Wherein Xi1～6 are 1～No. 6 sample abscissa value; Yi1～6 are 1～No. 6 sample ordinate value.
Formula 2:
Sim＝[(Xi-Xim)
2+(Yi-Yim)
2]
1/2
Sim is the administration group and the hypertension model of administration (contrast) is not organized distance; Xim, Yim are respectively the not hypertension model of administration (contrast) group X, Y coordinate mean value of i week.
Formula 3:
Sic＝[(Xi-Xic)
2+(Yi-Yic)
2]
1/2
Sic is the administration group and the normal control group distance of administration not; Xic, Yic are respectively not normal control group X, the Y coordinate mean value of administration of i week.
Formula 4:
Rd＝Sim/Sic
Rd be the administration group and the same period hypertension model group and the relative ratio of normal group distance; Sim is the administration group and the hypertension control group distance of administration not; Sic is the administration group and the normal control group distance of administration not.
The hypertension control group distance, administration group that can calculate administration group and administration not according to above-mentioned formula respectively and the normal control group distance of not administration and administration group and the same period hypertension model group and the relative ratio of normal group distance, the results are shown in Table 2.By table 2 administration group and the same period hypertension model group or the normal group distance results as can be known, 2,4,6,8 weeks after the Hypertensive Rats administration, from close hypertension model control group of initial stage, away from the normal control group, change into gradually away from the hypertension model control group, near the normal control group.From the administration group and the same period hypertension model group and the relative ratio of normal group distance can more obviously find out after the administration Hypertensive Rats gradually away from hypertension group, near the normal control group, therefore the clear and definite power of having represented that quantitatively medicine is regulated the internal metabolism group of this relative distance method, promptly quantitative response drug action.
Table 1 general ginsenoside administration group, hypertension control group and normal control group mediodespidine average (mmHg, n=6)
Relative distance between table 2 general ginsenoside administration group (TG) and the hypertension model group same period (SHR), the normal group (C)
*, Hypertensive Rats and normal control rat be (0 week) relative distance value before experiment.
Claims (10)
- One kind use metabonomic technology carry out the drug effect quantitative evaluation method relied on is the resulting metabolism group data of Instrument measuring, its feature comprises the following aspects:A) adopt serum to detect as sample;B) adopt the method for methanol extraction albumen that micromolecule in the serum is extracted;C) adopt the method for TMS trifluoroacetyl MSTFA that sample is carried out derivatization;D) adopt gas chromatography-flight time mass spectrum (GC/TOF-MS) to carry out sample analysis;E) use SIMCA P-11 software and offset minimum binary-discriminatory analysis (PLS-DA) and set up mathematical model;F) extracting parameter from the hyperspace mathematical model calculates relative distance between medication group and the control group.
- 2. require in 1 serum as the biological specimen except that right, biological specimen also can derive from people, animal, cell, tissue etc., specifically comprises whole blood, blood plasma, serum, urine, cerebrospinal fluid, saliva, tear, sweat, tissue homogenate, cell or cell culture fluid.
- 3. one of them group of above-mentioned biological specimen is to gather biological specimen (administration group) after the medication in the claim 2, and one group is control group; Control group can be an own control before the administration, also can be the model group parallel control of not administration, can also be the normal group contrast of not administration.
- 4. handle the biological specimen except that right requires the method for methanol extraction albumen in 1, also comprise through other albumen precipitation method, as adding the method for organic solvent (as ethanol, acetone, acetonitrile, isopropyl alcohol), various soda acid salt precipitation, microwave, thermal precipitation; Or carry out liquid-liquid through organic solvent and extract, organic solvent comprises ethyl acetate, chloroform, ether, normal butyl alcohol, sherwood oil, methylene chloride, benzene, normal hexane, cyclohexane, acetonitrile; Or the method for filtration/ultrafiltration; Or Solid-Phase Extraction method; Or biological specimen is without the method for pre-treatment.
- 5. require to adopt gas chromatography-flight time mass spectrum (GC/TOF-MS) to carry out the sample analysis in 1 except that right, also comprise other any analytical approach based on mass spectroscopy technology, nuclear magnetic resonance measuring technology and other metabolism group determination techniques.
- 6. resulting data can be the absolute quantitation data in the claim 1, also can the sxemiquantitative data, and as peak area, peak height, or the data that adopt mathematical method to calculate thus.
- 7. application SIMCA P-11 software and offset minimum binary-discriminatory analysis (PLS-DA) are set up the method for mathematical model in right requirement 1, also comprise other metabolism group data processing software, as all kinds of versions such as SPSS, Matlab, SIMCA-P; Comprise other method of selecting except that partial least square method-discriminatory analysis (PLS-DA), as quadrature partial least square method (OPLS), quadrature partial least square method-discriminatory analysis (OPLS-DA), principal component analysis (PCA) (PCA), Nonlinear Mapping (Nonlinemapping, NLM), cluster analysis methods such as (HCA) sets up mathematical model.
- 8. the mathematical model in the claim 1 can be dimension space model arbitrarily, and the hyperspace here can be 1,2,3 dimensions, also can be 4,5,6 even hyperspace more.
- In the claim 1 between medication group and the control group relative distance two kinds of account forms can be arranged, get the coordinate mean value of respectively organizing sample earlier, calculate again; When the own control sample is arranged, also can calculate each sample administration front and back earlier and change distance, averaging obtains again.
- 10. drug effect is represented to adopt relative distance between medicine group and the control group in the claim 9, also can be the function calculation value of relative distance, and as usual have any mathematical computations mode gained results such as logarithm value, natural logarithm value, square value, square root.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102622532A (en) * | 2012-02-27 | 2012-08-01 | 中国药科大学 | Method for building complex drug material group in vivo and vitro associated metabolic network |
| CN102788849A (en) * | 2012-06-01 | 2012-11-21 | 中国人民解放军第二军医大学 | Novel method for chromatography-mass spectrometry metabolomics data analysis |
| CN107764848A (en) * | 2016-08-18 | 2018-03-06 | 中国科学院烟台海岸带研究所 | A kind of method utilized based on metabolism group evaluation epinephelus feed |
| CN107884495A (en) * | 2017-11-14 | 2018-04-06 | 中国科学院昆明植物研究所 | A kind of quick method for finding natural products effective substance |
| CN109085262A (en) * | 2018-08-03 | 2018-12-25 | 杭州佰勤医疗器械有限公司 | Serum plasma pharmaceutical extraction composition and application thereof |
| CN113655134A (en) * | 2021-07-06 | 2021-11-16 | 杭州师范大学 | Metabonomics analysis method for treating hypertension caused by high-fat diet in rat serum |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102622532A (en) * | 2012-02-27 | 2012-08-01 | 中国药科大学 | Method for building complex drug material group in vivo and vitro associated metabolic network |
| CN102788849A (en) * | 2012-06-01 | 2012-11-21 | 中国人民解放军第二军医大学 | Novel method for chromatography-mass spectrometry metabolomics data analysis |
| CN102788849B (en) * | 2012-06-01 | 2013-11-13 | 中国人民解放军第二军医大学 | Novel method for chromatography-mass spectrometry metabolomics data analysis |
| CN107764848A (en) * | 2016-08-18 | 2018-03-06 | 中国科学院烟台海岸带研究所 | A kind of method utilized based on metabolism group evaluation epinephelus feed |
| CN107884495A (en) * | 2017-11-14 | 2018-04-06 | 中国科学院昆明植物研究所 | A kind of quick method for finding natural products effective substance |
| CN109085262A (en) * | 2018-08-03 | 2018-12-25 | 杭州佰勤医疗器械有限公司 | Serum plasma pharmaceutical extraction composition and application thereof |
| CN113655134A (en) * | 2021-07-06 | 2021-11-16 | 杭州师范大学 | Metabonomics analysis method for treating hypertension caused by high-fat diet in rat serum |
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Application publication date: 20100811 |