WO2017054609A1 - 联用药药效的处理方法和处理装置 - Google Patents

联用药药效的处理方法和处理装置 Download PDF

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WO2017054609A1
WO2017054609A1 PCT/CN2016/097514 CN2016097514W WO2017054609A1 WO 2017054609 A1 WO2017054609 A1 WO 2017054609A1 CN 2016097514 W CN2016097514 W CN 2016097514W WO 2017054609 A1 WO2017054609 A1 WO 2017054609A1
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dose
effect
drug
curve
combination
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PCT/CN2016/097514
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English (en)
French (fr)
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袁守军
李琳娜
杨德宣
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中国人民解放军军事医学科学院放射与辐射医学研究所
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Priority to JP2018517325A priority Critical patent/JP6574522B2/ja
Priority to EP16850233.4A priority patent/EP3358481B8/en
Priority to US15/764,334 priority patent/US11205502B2/en
Publication of WO2017054609A1 publication Critical patent/WO2017054609A1/zh

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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H70/00—ICT specially adapted for the handling or processing of medical references
    • G16H70/40—ICT specially adapted for the handling or processing of medical references relating to drugs, e.g. their side effects or intended usage
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
    • G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
    • G16C20/30—Prediction of properties of chemical compounds, compositions or mixtures
    • G—PHYSICS
    • G06—COMPUTING; CALCULATING OR COUNTING
    • G06N—COMPUTING ARRANGEMENTS BASED ON SPECIFIC COMPUTATIONAL MODELS
    • G06N7/00—Computing arrangements based on specific mathematical models
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
    • G16H20/10—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16Z—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS, NOT OTHERWISE PROVIDED FOR
    • G16Z99/00—Subject matter not provided for in other main groups of this subclass

Definitions

  • the present invention relates to the field of biomedicine, and in particular to a method and a treatment device for the efficacy of a combination drug.
  • the basic path of new drug research and development is to target a disease-related target, to screen candidate compounds and optimize the lead, and then to conduct drug-based research, pre-clinical evaluation and clinical trial before approval.
  • This research model based on "single target, single disease, single drug", especially the development of single structural compound drugs targeting a single target, is becoming more and more difficult in therapeutic use.
  • the cause of many refractory major diseases is usually multi-target, multi-link, and it needs to be effective for multiple links. It is almost impossible to develop new compounds for single structures with multiple links. From the feasibility and practical effect of solving the problem, giving patients a combination of drugs or developing new compound drugs is a broad path for disease treatment and new drug development.
  • the combination of drugs is one of the most effective treatments for diseases.
  • traditional Chinese medicine a combination of various animal and plant or mineral components, or a fixed formula is more common.
  • the motivations for multi-drug combination include: treatment of diseases, often need to target multiple links or target multiple targets; patients often have multiple diseases; treatment of any disease requires treatment for treatment and symptomatic treatment; adaptation of any drug
  • the disease and treatment window are limited and have different properties and varying degrees of toxic side effects. Therefore, the purpose of the combination is to achieve maximum therapeutic effect and to minimize toxic side effects.
  • the layers of interaction between drugs include the following: 1) The interaction of the physical properties of the drug refers to the change in the physical and chemical properties of the drug when it is compatible and combined. The national drug authorities have strict regulations on the compatibility of drugs used in clinical practice, such as drug contraindications. 2) The mutual influence on the body's metabolic disposal ability refers to a drug that affects the body's tissues and organs responsible for drug metabolism, and has an important effect on the in vivo process of another drug, which in turn causes changes in drug efficacy and toxicity. The guiding principles for the effects of drug interactions promulgated by the drug administrations at home and abroad are aimed at this part.
  • the interaction between drug effects refers to the enhancement or attenuation of drug effects when drugs with different or similar mechanisms of action are combined.
  • the influence of the order of administration (sequential), the combination of multiple drugs may occur in the order of administration, and the changes in the state of the cells caused by the cells may be different, thereby causing a difference in drug effects.
  • the drug administration department has clear management guidelines for the former two, and there is no specific guidance for the synergistic, additive and quantitative detection of drug synergies in the latter two. Regardless of the level at which the drug interaction occurs, the effects of the drug change, synergistic, additive, and antagonistic.
  • synergy is the additive effect of actual drug effect greater than expected.
  • Addition is the additive effect of actual drug effect equal to expectation.
  • Antagonism is that the actual drug effect is less than expected. Additive effect. From the perspective of drug effect, synergy and antagonism are actually interactions between drugs; when added, no interaction occurs, so the definition of drug addition extends to zero interaction.
  • synergy is at a level of equal efficacy, the dose of the drug is less than the expected combined dose; and at the same level of efficacy, the dose of the drug is equal to the expected combined dose;
  • Antagonism is that at the same level of efficacy, the combined dose of the drug is greater than the expected combined dose. Therefore, the effects caused by multi-drug combination and the change in dosage are actually two sides of a coin, which can be used to define synergy, addition and antagonism caused by multi-drug combination.
  • the expected additive effect of a certain combination of drugs is a certain value.
  • the synergy, addition and antagonism are quantitatively calculated and judged by comparing the actual effect detection value at the time of use with the value of the expected additive effect.
  • the dose-response curves of each drug member and combination drug are complicated. Taking the combination of two drugs A and B as an example, the actual situation of the drug members and the complexity of the dose-effect relationship curve are complicated. , listed below:
  • Case 1 Drug A has an effect, Drug B has no effect, and Drug A and B are combined, and the effect of Drug A changes significantly.
  • the dose-response curve of the expected additive effect of the two drugs is the dose-effect curve of the drug A alone, and it is easier to quantify the synergistic effect or antagonistic effect of the combined use of the drug.
  • Case 2 Both drug A and drug B have no effect, and drug A and drug B are combined to produce a drug effect.
  • the expected drug additive effect curve of the combination of the two drugs is a straight line with zero effect value, and it is easier to quantify the synergistic effect of the combined application of the drug.
  • Case 3 Drug A has an effect, and Drug B also has an effect.
  • Drug A and B are combined, the respective drug effects are inevitably changed. It is different from the effect of drug A alone, and the effect of drug B alone.
  • the dose-response curves of each drug member are established separately and interact with each other. It is very difficult to determine the expected additive effect curve.
  • the dose-response curves for the drugs are:
  • Drug A the dose-effect curve of drug B when combined with drug B at a fixed dose
  • Drug B the dose-response curve of drug A when combined with drug A at a fixed dose.
  • Loewe's equivalent line addition model is specifically: the two drugs A and B, the drug doses D A and D B at a certain effect level are respectively marked on the X-axis and the Y-axis in the Cartesian coordinate system, connecting two The straight line of the point gives the intercepted linear equation as: Loewe pointed out that when the two drugs are combined in a small dose of d A and d B respectively, and the effect of the single drug dose D A or D B is reached, the following relationship exists:
  • the Bliss independent model is specifically: the effects of drug A and drug B are qualitative data, and the magnitude of the drug effect ranges from 0 to 1.
  • P AB P A +P B -P A ⁇ P B
  • E AB E A +E B –E A ⁇ E B
  • the Bliss independent model method introduces the probability addition formula for the joint application analysis of qualitatively reactive drugs.
  • this method lacks the support of the dose-effect relationship of each of drug A and drug B, and only considers the combination of the two drugs as the sum of the probability of occurrence of two isolated events.
  • the Jin's method which is used more frequently in China, is derived from the model, but the model does not conform to the basic law of dose-effect relationship of drugs.
  • the main object of the present invention is to provide a pharmacological treatment method and a treatment device for a combination drug, which solve the technical problem that it is difficult to determine the drug effect when a plurality of drugs are used in combination in the prior art.
  • the combination drug refers to a plurality of drugs for combination use, and the combination drug contains different kinds of drugs depending on the kind of the drug to be used in combination.
  • the combination drug refers to two drugs; when the three drugs are used in combination, the combination drug refers to three drugs; when three or more drugs are used in combination, the combination drug refers to three or more drugs. a variety of medicines.
  • the combination, the combination, the combined application, and the compatibility all mean the combination.
  • the combination group in which the specific different drugs in the examples are formed according to different combination conditions is also a meaning of the combination.
  • Dose-effect relationship It means that within a certain dose range, the dose of the drug is proportional to the drug effect. This relationship is called dose-effect relationship, which is called dose-effect relationship.
  • Dose-response relationship curve A curve that reflects the regularity of the drug effect as a function of drug dose or concentration.
  • Dosage index On the abscissa axis, along a certain combined dose point, make a vertical line, and the intersecting dose-effect curve is the minimum and maximum values of the expected additive effect at the combined dose. The actual pharmacodynamic values of the combined doses were compared with the maximum and minimum values of the additive efficacy values, respectively, and CI d1 and CI d2 were calculated.
  • Effect-use index on the ordinate axis, along a certain determined point of effect, a straight line parallel to the horizontal axis, intersecting the dose-effect curve is the minimum dose given by the expected additive effect at the efficacy level. Value and maximum value. The combined doses that produced the actual level of efficacy were compared to the minimum and maximum values of the added doses, respectively, to calculate CI e1 and CI e2 .
  • a method for treating a drug efficacy comprising: obtaining a dose-effect curve of an expected additive effect of a combination drug, and the dose-effect curve is composed of a plurality of The outermost two envelops in the equivalent dose-effect curve, the equivalent dose-effect curve refers to the dose of a certain target component in the combination drug as the abscissa, and the equivalent conversion of the combination drug to any one group of drugs.
  • the expected additive effect obtained is a curve established on the ordinate; the equivalent exchange is equivalently exchanged according to the order of administration of each component in the obtained combination drug; the actual effect value of the combined drug is obtained according to a certain combination
  • the actual dose-effect relationship curve formed by the dose change of a target component drug; comparing the positional relationship between the actual dose-effect relationship curve and the dose-effect curve band, and when the actual dose-effect relationship curve is located above the dose-effect curve band, the combination drug is used
  • the efficacy output is synergistic; when the actual dose-effect curve is below the dose-effect curve, the pharmacodynamic output of the combination is antagonized; when the actual dose-effect curve is within the range of the dose-effect curve, it will be used together.
  • the efficacy of the addition output is synergistic; when the actual dose-effect curve is below the dose-effect curve, the pharmacodynamic output of the combination is antagonized; when the actual dose-effect curve is within the range of the dose-effect curve, it will
  • the combination method includes the first component drug A and the second component drug B
  • the processing method further comprises establishing a plurality of equivalent dose-effect curves before the step of obtaining the dose-effect curve of the expected additive effect of the combination drug.
  • the processing method further comprises: calculating the actual dose-effect relationship curve corresponding to the upper portion of the dose-effect curve a first dose range of a target component drug; and outputting the first dose range as a synergistic dose range for a target component drug.
  • the processing method further comprises: obtaining a joint relationship between a target component drug and the remaining component drugs in the combined drug; calculating the joint according to the joint relationship The synergistic dosage range of the remaining components of the drug under combined conditions; and the synergistic dosage range of the remaining component drugs.
  • the processing method further comprises: calculating the actual dose-effect relationship curve corresponding to the lower part of the dose-effect curve band The second dose range of a certain target component drug, and the second dose range is output as a range of antagonist amounts of a certain target component drug.
  • the processing method further comprises: obtaining a joint relationship between a target component drug and the remaining component drug in the combined drug; calculating the joint according to the joint relationship The range of the amount of the antagonist under the combined conditions of the remaining components of the drug; and the range of the amount of the antagonist that outputs the remaining component drug.
  • the processing method further comprises: calculating the actual dose-effect relationship curve within the range of the dose-effect curve The third dose range of the corresponding target component drug; and the third dose range is output as the additive dose range of a certain target component drug.
  • the processing method further comprises: obtaining a joint relationship between a target component drug and the remaining component drugs in the combined drug; calculating according to the joint relationship The additive dose range of the remaining components of the combination drug under combined conditions; and the added dose range of the remaining component drugs.
  • the step of comparing the positional relationship between the actual dose-effect relationship curve and the dose-effect curve includes: obtaining an expected addition of the corresponding combination drug in the range of the dose-effect curve at a specific combination dose. The minimum and maximum value of the effect; the actual effect value of the corresponding combination drug on the actual dose-effect relationship curve at a specific combination dose; the minimum value of the actual effect value and the expected additive effect is calculated.
  • a first ratio; a second ratio of the actual effect value to the maximum value of the expected additive effect; the first ratio and the second ratio are labeled CI d1 and CI d2 , respectively; if CI d1 and CI d2 are both greater than 1, It is determined that the actual dose-effect relationship curve is located above the dose-effect curve; the combination is synergistic. If CI d1 and CI d2 are both less than 1, it is determined that the actual dose-effect relationship curve is below the dose-effect curve; the combination is antagonistic. If any of CI d1 and CI d2 is ⁇ 1 or ⁇ 1, it is determined that the actual dose-effect relationship curve is within the range of the dose-effect curve.
  • the processing method further includes the step of outputting CI d1 and CI d2 .
  • the step of comparing the positional relationship between the actual dose-effect relationship curve and the dose-effect curve includes: obtaining a minimum value and a maximum dose of a target component drug corresponding to the combination effect of the combination drug on the dose-effect curve Value; obtain the actual combined dose required for the combination to produce a specific effect on the actual dose-effect relationship curve; calculate a third ratio of the actual combined dose to the minimum; calculate a fourth ratio of the actual combined dose to the maximum;
  • the third ratio and the fourth ratio are respectively labeled as CI e1 and CI e2 ; if both CI e1 and CI e2 are less than 1, it is determined that the actual dose-effect relationship curve is above the dose-effect curve; if CI e1 and CI e2 are both greater than 1, it is determined that the actual dose-effect relationship curve is located below the dose-effect curve; if any of CI e1 and CI e2 is ⁇ 1 or ⁇ 1, it is determined that the actual dose-effect relationship curve is within the range of
  • the processing method further includes the step of outputting CI e1 and CI e2 .
  • a treatment device for co-medication comprising: a first acquisition module, a dose-effect curve for obtaining an expected additive effect of the combination, and a dose-effect curve It is composed of two outermost two of the equivalent dose-effect curves.
  • Each equivalent dose-effect curve refers to the dose of a certain target component in the combination drug as the abscissa, and the equivalent conversion of the combination drug is
  • the expected additive effect obtained by any one of the drugs is a curve established on the ordinate; the equivalent exchange is equivalently exchanged according to the order of administration of the components in the combination; the second acquisition module is used to obtain the combination drug The actual dose-effect curve formed by the dose change of a certain target component in the combination drug;
  • the first comparison module is used to compare the positional relationship between the actual dose-effect relationship curve and the dose-effect curve, and the first An output module, configured to output the synergistic effect of the combined drug as synergy when the actual dose-effect relationship curve is located above the dose-effect curve; and the second output module is configured to when the actual dose-effect relationship curve is located below the dose-effect curve
  • Antagonistic efficacy of drug output third output means for when the actual curve lies within the dose-response relationship curve with a dose range, the drug efficacy is
  • the combination medicine comprises a first component drug A and a second component drug B
  • the processing device further comprises an equivalent dose effect curve establishing module
  • the equivalent dose effect curve establishing module is configured to obtain the combined drug in the first obtaining module
  • a plurality of equivalent dose-effect curves are established before the step of the dose-effect curve of the additive effect
  • the equivalent dose value Bm corresponding to the effect value g(Bm) of the second component
  • the processing device further includes: a first calculating module, configured to: after the first output module outputs the drug efficacy of the combined drug as a synergy, calculate a corresponding one when the actual dose-effect relationship curve is located above the dose-effect curve band a first dose range of the target component drug; and a fourth output module for outputting the first dose range as a synergistic dose range for a target component drug.
  • a first calculating module configured to: after the first output module outputs the drug efficacy of the combined drug as a synergy, calculate a corresponding one when the actual dose-effect relationship curve is located above the dose-effect curve band a first dose range of the target component drug.
  • the processing device further includes: a third acquiring module, configured to acquire a target component drug in the combined drug after the fourth output module outputs the first dose range as a synergistic dose range of a certain target drug a combination relationship between the remaining components; a second calculation module for calculating a synergistic dose range of the remaining components of the combination in combination according to the combined relationship; and a fifth output module for outputting the rest The synergistic dosage range of the component drugs.
  • a third acquiring module configured to acquire a target component drug in the combined drug after the fourth output module outputs the first dose range as a synergistic dose range of a certain target drug a combination relationship between the remaining components
  • a second calculation module for calculating a synergistic dose range of the remaining components of the combination in combination according to the combined relationship
  • a fifth output module for outputting the rest The synergistic dosage range of the component drugs.
  • the processing device further includes: a third calculating module, configured to: after the second output module outputs the pharmacodynamic effect of the combined drug as antagonism, calculate a corresponding one when the actual dose-effect relationship curve is located below the dose-effect curve band a second dose range of a target component drug, and a sixth output module for outputting the second dose range as a range of antagonist amounts for a target component drug.
  • a third calculating module configured to: after the second output module outputs the pharmacodynamic effect of the combined drug as antagonism, calculate a corresponding one when the actual dose-effect relationship curve is located below the dose-effect curve band a second dose range of a target component drug, and a sixth output module for outputting the second dose range as a range of antagonist amounts for a target component drug.
  • the processing device further includes: a fourth obtaining module, configured to obtain a target component drug in the combined drug after the sixth output module outputs the second dose range as an antagonist amount range of the target component drug a combination relationship between the remaining components; a fourth calculation module for calculating a range of antagonist amounts of the remaining components of the combination in combination according to the combined relationship; and a seventh output module for outputting the rest The range of antagonist amounts of the component drug.
  • a fourth obtaining module configured to obtain a target component drug in the combined drug after the sixth output module outputs the second dose range as an antagonist amount range of the target component drug a combination relationship between the remaining components
  • a fourth calculation module for calculating a range of antagonist amounts of the remaining components of the combination in combination according to the combined relationship
  • a seventh output module for outputting the rest The range of antagonist amounts of the component drug.
  • the processing device further includes: a fifth calculating module, configured to: after the third output module outputs the combined effects of the drug effects of the combined drugs, calculate a corresponding one when the actual dose-effect relationship curve is within the range of the dose-effect curve a third dose range of a target component drug; and an eighth output module for outputting the third dose range as an additive dose range of a target component drug.
  • a fifth calculating module configured to: after the third output module outputs the combined effects of the drug effects of the combined drugs, calculate a corresponding one when the actual dose-effect relationship curve is within the range of the dose-effect curve a third dose range of a target component drug
  • an eighth output module for outputting the third dose range as an additive dose range of a target component drug.
  • the processing device further includes: a fifth obtaining module, configured to obtain a target component drug in the combined drug after the eighth output module outputs the third dose range as the additive dose range of a certain target component drug a combination relationship with the remaining component drugs; a sixth calculation module for calculating an additive dose range of the remaining components of the combination drug under the combined condition according to the combined relationship; and a ninth output module for The additive dose range of the remaining component drugs is output.
  • a fifth obtaining module configured to obtain a target component drug in the combined drug after the eighth output module outputs the third dose range as the additive dose range of a certain target component drug a combination relationship with the remaining component drugs
  • a sixth calculation module for calculating an additive dose range of the remaining components of the combination drug under the combined condition according to the combined relationship
  • a ninth output module for The additive dose range of the remaining component drugs is output.
  • the first comparison module includes: a first acquisition sub-module, configured to obtain a minimum value of the expected additive effect of the corresponding combination drug in the range of the dose-effect curve under a specific combined dose of a certain target component drug And a maximum value; a second acquisition sub-module, configured to obtain an actual effect value of a corresponding combination drug on a practical dose-effect relationship curve at a specific combined dose; the first calculation sub-module is used for Calculating a first ratio of the actual effect value to the minimum value of the expected additive effect; a second calculation sub-module for calculating a second ratio of the actual effect value to the maximum value of the expected additive effect; the first marker sub-module for The first ratio and the second ratio are respectively labeled as CI d1 and CI d2 ; the first determining sub-module is configured to determine that the actual dose-effect relationship curve is above the dose-effect curve when both CI d1 and CI d2 are greater than one; a second determining submodule, configured to determine that
  • the output processing apparatus further comprising eleventh means for marking a first sub-module in the first ratio and the second ratio are labeled CI d1 and CI d2, and outputs CI d1 CI d2.
  • the first comparison module includes: a third acquisition sub-module, configured to obtain a minimum value and a maximum value of a dose of a certain target component drug corresponding to the specific effect produced by the combination drug on the dose-effect curve; Obtaining a sub-module for obtaining the actual combined dose required for the combined effect to produce a specific effect on the actual dose-effect relationship curve; a third calculating sub-module for calculating a third ratio of the actual combined dose to the minimum value; a fourth calculation sub-module for calculating a fourth ratio of the actual combined dose to the maximum value; a second marking sub-module for marking the third ratio and the fourth ratio as CI e1 and CI e2 respectively ; the fourth determining sub-module For determining that the actual dose-effect relationship curve is above the dose-effect curve when both CI e1 and CI e2 are less than 1, and the fifth determining sub-module for determining the actual amount when both CI d1 and CI d2 are greater than one.
  • the effective relationship curve is located below the dose-effect curve; and the sixth determining sub-module is used to determine that the actual dose-effect relationship curve is within the range of the dose-effect curve when any one of CI d1 and CI d2 is ⁇ 1 or ⁇ 1 .
  • the processing device further includes a twelfth output module, configured to output CI d1 and CI d2 after the second marker submodule marks the third ratio and the fourth ratio as CI e1 and CI e2 respectively.
  • a storage medium is provided.
  • the above storage medium is used to store the program code executed by any of the above-described combination drug efficacy treatment methods.
  • a computer terminal comprising: one or more processors, a memory, and a transmission device, wherein the memory is configured to store a drug-effect processing method and/or a program corresponding to the device.
  • the processor executes the various functional applications and data processing by executing program instructions and/or modules stored in the memory to implement the above-described combined drug efficacy processing method.
  • the pharmacodynamic treatment method of the embodiment combines the difference in the order of administration of the plurality of drugs in combination and the dose-effect relationship of different drugs.
  • the effects of different combinations of drugs can not only achieve the detection of multiple (two or more) drugs, but also enable quantitative detection.
  • the above treatment method not only solves the problem that the efficacy of the multi-drug combination in the prior art cannot be accurately detected, but also the efficacy of the detected combination drug can be widely applied in the research and development, toxicology research and environmental evaluation of the compound medicine.
  • FIG. 1 is a schematic flow chart showing a method for treating a pharmacological effect of a combination drug in a preferred embodiment of the present application
  • FIG. 2 is a schematic view showing the structure of a pharmacodynamic treatment device for a combination drug in a preferred embodiment of the present application
  • FIG. 3A to 3D are graphs showing the dose-effect relationship of the drug NX in the monohydroxy compound (NX) and the paclitaxel (TX) single-use and combination group according to Example 1 of the present application; wherein, FIG. 3A to FIG. 3B respectively The dose-effect relationship curves of the two single drugs of nitrate compound (NX) and paclitaxel (TX) are shown; FIG. 3C shows the actual pharmacodynamics of the combined group with the drug NX when NX+TX is used in a fixed ratio. The dose-effect relationship curve of the dose change; FIG. 3D shows the dose-effect relationship curve of the actual pharmacodynamics of the combined group with the dose change of the drug NX when the NX different dose + TX fixed dose is used together;
  • FIG. 4 shows that when NX+TX is used in a fixed ratio in the first embodiment of the present application, the NX dose levels of the combined group are plotted on the abscissa, and the expected additive effect values are plotted on the ordinate to form the expected phase.
  • FIG. 5 shows the specific combined dose points of the combination of multiple NX+TXs when the NX+TX is combined at a fixed ratio in FIG. 4, and then the NX dose levels of the combined group are plotted on the abscissa. It is expected that the additive effect value and the actual effect value are plotted on the ordinate, and the dose-effect curve and the actual dose-effect relationship curve which constitute the expected additive effect;
  • Figure 6 shows that the intersection dose points at the ED 50 efficacy level and the expected additive effect in Figure 5 above are A and B, and the intersection point with the actual effect is C, and the actual effect of the intersection dose point is greater than the expected additive effect.
  • the dose range point located below the dose-effect curve;
  • FIG. 7 shows that when the TX fixed concentration + NX different ratios are used in the first embodiment of the present application, the NX dose levels of the combined group are plotted on the abscissa, and the expected additive effect values are plotted on the ordinate to form the expected phase.
  • FIG. 8A to 8D show the etoposide in the monotherapy and drug combination group of the three drugs etoposide (A), vincristine (B) and 5-fluorouracil (C) according to Example 2 of the present application.
  • Figure 9A shows the expected addition of three (A+B)+C, (A+C)+B, (B+C)+A combinations at each dose level of the etoposide (A) in the combined group.
  • the data of the effect value and the actual effect value are the ordinate, and 12 dose-effect curves and actual dose-effect curves are made;
  • Figure 9B shows the combination of three (A+B)+C, (A+C)+B, (B+C)+A in each dose level of etoposide (A) in the combined group.
  • the data of the expected additive effect value and the actual effect value are the ordinate, and the dose-effect curve and the actual dose-effect curve surrounded by the two outermost curves of the 12 dose-effect curves are made;
  • the method provided by the embodiments of the present application can be executed in a mobile terminal, a computer terminal, or the like.
  • the method for detecting the efficacy of the multi-drug combination described above can be applied to a network environment.
  • the above-described multi-drug combination drug efficacy detecting method can be applied to a hardware network environment constituted by a terminal and a server.
  • the terminal connects to the server through a network, including but not limited to: a wide area network, a metropolitan area network, or a local area network.
  • the terminal may be a mobile terminal or a personal computer.
  • the terminal may be a terminal such as a smart phone, a tablet computer, or a PDA.
  • the present application provides a method for treating the efficacy of the combination drug as shown in FIG. 1 is a flow chart of a method of treating the efficacy of a combination drug in accordance with an embodiment of the present application.
  • the processing method includes the following steps:
  • Step S202 obtaining a dose-effect curve of the expected additive effect of the combination drug, the dose-effect curve band is surrounded by two outermost two of the equivalent dose-effect curves, and each equivalent dose-effect curve refers to the combination drug.
  • the dose of a certain target component drug is the abscissa, and the curve obtained by the equivalent additive effect obtained by equivalent exchange of the drug into any one group of drugs is the ordinate; the equivalent exchange is in accordance with the obtained combination drug. Equivalent exchange of the order of administration of each component;
  • Step S204 obtaining an actual dose-effect relationship curve formed by the actual effect value of the combination drug according to the dose change of a certain target component drug in the combination drug;
  • Step S206 comparing the positional relationship between the actual dose-effect relationship curve and the dose-effect curve band, and
  • Step S208 when the actual dose-effect relationship curve is located above the dose-effect curve, the drug effect output of the combination drug is synergistic; when the actual dose-effect relationship curve is located below the dose-effect curve, the drug effect output of the combination drug is used. For antagonism; when the actual dose-effect relationship curve is within the range of the dose-effect curve, the drug effect output of the combination drug is added.
  • the order of administration of each component in the obtained combination drug includes a combined dose or concentration of each component drug, and a dose-effect relationship curve of each component drug.
  • the above treatment method of the present application compares the actual dose-response curve of the combination drug based on the dose-effect curve based on the expected additive effect of the combination drug, and then judges the relationship by the positional relationship between the actual dose-effect curve and the dose-effect curve band.
  • the efficacy of medication Since the dose-effect curve is more in line with the dose-effect relationship of the drug and the pharmacodynamic basic characteristics of the drug combination, the pharmacodynamic treatment method of the embodiment combines the difference in the order of administration of the plurality of drugs in combination and the dose-effect relationship of different drugs.
  • the effects of different combinations of drugs can not only achieve the detection of multiple (two or more) drugs, but also enable quantitative detection.
  • the above treatment method not only solves the problem that the efficacy of the multi-drug combination in the prior art cannot be accurately detected, but also the efficacy of the detected combination drug can be widely applied in the research and development, toxicology research and environmental evaluation of the compound medicine.
  • the expected additive effect of the combination drug is equivalently converted into the expected additive effect of each component drug, and then each is established.
  • the equivalent dose-effect curve formed by the expected additive effect of the strip drug with the dose change of a certain target component drug, and then the two outermost curved bands of the plurality of equivalent dose-effect curves are obtained to obtain the joint.
  • the dose-effect curve of the expected additive effect of the drug; at the same time or after obtaining the above-mentioned dose-effect curve, the actual dose-effect relationship of the actual effect value of the combination drug with the dose change of a certain target drug in the combination drug is obtained.
  • Curve then compare the positional relationship between the dose-effect curve and the actual dose-effect curve. According to the actual dose-effect curve, it is located above, below or within the range of the dose-effect curve. Correspondingly, the efficacy of the output combination drug is synergistic and antagonistic. Or add.
  • the equivalent additive effect of each combination is equivalently converted to the equivalent dose-effect curve of each component.
  • the dose-response curve of the expected additive effect of the combination drug is the same as the dose-response curve of each component drug itself, since the additive effect is a zero interaction, when each drug is simultaneously exposed to the body tissue, the efficacy is performed. In the unit, the order in which the effects of the drug work is random.
  • the expected additive effect of the combination drug is the sum of the effects of all drug efficacy units.
  • the pharmacodynamic performance of a pharmacodynamic performance unit is in the order that B exerts its own dose effect along B's own dose-effect curve on the basis of the effect of the first component A;
  • the other efficacy-executing unit may appear to exert the effect of self-dose along A's own dose-effect curve based on the effect of the second component B.
  • Expressed by the formula is:
  • the function values representing the units in the set shall be arranged from low to high; Bn and An are equivalent doses, and Am and Bm are equivalent doses.
  • the expected additive effect value is a range, that is, a set of numbers, and the two expected additive effect values are the boundary values of the set, which represent all
  • the efficacy unit of the drug is 100% Am ⁇ Bn and 100% Bn ⁇ Am
  • the intermediate value range is the sum of the cumulative effects of different ratios of Am ⁇ Bn and Bn ⁇ Am pharmacodynamics. It is expected that the additive effect value is more in line with the dose-effect curve relationship within the range of the number set, rather than a straight line in the prior art.
  • the combination method includes a first component drug A and a second component drug B
  • the processing method further comprises establishing a plurality of steps before the step of obtaining a dose-effect curve band of the expected additive effect of the combination drug.
  • the above process of establishing the equivalent dose-effect curve is equivalently converting the effect produced by the combined dose of the first component A to the second component B, and the equivalent additive effect of the combined drug is equivalently converted into the second.
  • the dose of the component B and the corresponding effect value similarly, when the effect produced by the combined dose of the second component B is equivalently converted into the first component A, the above steps are repeated, and then the process is established.
  • the equivalent dose-effect curve is to equivalently convert the effect produced by the combined dose of the second component B to the first component drug A, and equivalently convert the expected additive effect of the combination drug into the first component drug.
  • the dose of A and the corresponding effect value is to equivalently convert the effect produced by the combined dose of the second component B to the first component drug A, and equivalently convert the expected additive effect of the combination drug into the first component drug.
  • the equivalent dose-effect curve of the expected additive effect of the combination has the above two. Then, the dose-effect curve surrounded by the above two equivalent dose-effect curves is the dose-effect curve of the expected additive effect when the two drugs are combined.
  • the procedure for establishing the equivalent dose-effect curve of the expected additive effect of the combination of the two drugs is the same, and the expected additive effect of the three drugs is based on the additive effect of any two drugs, and the third drug is along the third drug.
  • Your own dose-effect curve reaches your own dose of medicine
  • the effect level that is, the expected additive effect of the combination drug and the dose-response curve of the third drug are equivalent dose exchange, the equivalent dose is combined with the third drug dose, following the dose-effect relationship function of the third drug
  • the resulting function value is the expected additive effect value of the three drugs.
  • the dose-effect curves of the two additional drugs along their own additive effects reach the efficacy level of the self-dose.
  • the additive effect of any two of the drugs is the expected additive effect band obtained when the combination drug contains the first component drug A and the second component drug B. That is to say, the expected additive effect of the combination of the three drugs is based on the equivalent dose-effect curve of any two drugs according to their combined dose to one of the components, and the third drug is along itself. The dose-effect curve reaches the level of efficacy of the self-dose. vice versa.
  • Drug a, drug b and drug c have three different combinations of drug sequences, respectively (a+b)+c, (a+c)+b, (b+c)+a, in each drug sequence combination
  • the expected additive effect of the sequential combination of +c can be equivalent to (a+b) equivalently converted to the equivalent dose-effect curve of c, or equivalently converted to the equivalent dose-effect curve of (a+b)
  • the equivalent dose-effect curve of (a+b) can be equivalently converted to the equivalent dose-effect curve of a, and can also be converted into the equivalent dose-effect curve of b, thus the combination of (a+b)+c
  • the additive effect has four equivalent dose-effect curves; according to the above-mentioned combination of drugs, the process of establishing the above equivalent dose-effect curve
  • the equivalent conversion between the two drugs is established to establish the equivalent dose effect.
  • the steps of the curve, and thus the steps of establishing the equivalent dose-effect curve described in the above embodiments cover the steps common to all of the combinations of ⁇ 2 in establishing the equivalent dose-effect curve, thus obtaining n (n ⁇ 2)
  • any step of using the above-described equivalent dose-effect curve is within the scope of the present application.
  • the processing method further comprises: calculating the actual dose-effect relationship curve above the dose-effect curve a first dose range of the corresponding target component drug; and outputting the first dose range as a synergistic dose range of a target component drug.
  • the dose of a target component drug at the intersection of the actual dose-effect curve and the dose-effect curve can be calculated, and the dose can be calculated according to the dose.
  • a first dose range corresponding to the synergistic effect located above the intersection is obtained.
  • the processing method further includes: obtaining a combination relationship between a target component drug and the remaining component drug in the combination drug; Calculate a synergistic dosage range for the remaining components of the combination in combination; and a synergistic dose range for the remaining components.
  • obtaining a combination relationship between a target component drug and the remaining component drug in the combination drug can be obtained according to a combination relationship of the components in the previously obtained combination drug.
  • the combination is three, A, B, and C
  • A is the target component drug
  • the dose at the intersection of the expected additive effect band and the actual dose-effect relationship curve of the three drugs it can be calculated that when the drug effect of the combination drug is synergistic, the A component drug
  • the synergistic dosage range; according to the ratio of the ratio of the A component drug to the B component drug, the synergistic dosage range of the B component drug can be obtained; similarly, according to the A component drug and the C component drug A 2:5 ratio can also give a synergistic dose range for the C component.
  • the synergistic dosage range of the remaining components can also be obtained depending on the specific combination conditions. For example, when A and B are combined, in which A is combined with a different concentration ( ⁇ g/ml) of B drug ⁇ g/ml at a fixed concentration of 1 ng/ml, the synergistic dose of the target drug B is calculated. In the range, the synergistic dose range of the A-component drug is the combined fixed dose.
  • the synergistic dose ranges of the respective components are added, and the synergistic dose range of the synergistic drug can be obtained.
  • the synergistic dose range of the above target drugs and the related dose combination index and/or effect combination index may also be obtained according to the research and development of the compound medicine, toxicology research and environmental evaluation.
  • the processing method further comprises: calculating the actual dose-effect relationship curve below the dose-effect curve
  • the second dose range of the corresponding target component drug is output, and the second dose range is output as the antagonist amount range of a certain target component drug.
  • the calculation method of calculating the second dose range of a certain target component drug corresponding to the actual dose-effect relationship curve under the dose-effect curve may also be located at the intersection of the dose-effect curve according to the actual dose-effect relationship curve.
  • the dose corresponding to the space, and then the range of doses below which the effect is located, is the range of the amount of antagonist for a target component drug.
  • the range of antagonists of the target drug can also be obtained according to the development of the compound drug, toxicology research, and environmental assessment.
  • the method further includes: obtaining a combination relationship between a target component drug and the remaining component drug in the combination drug; Calculate the range of the amount of the antagonist under the combined conditions of the remaining components of the combination; and the range of the amount of the antagonist that outputs the remaining components.
  • the range of the antagonist amount of the remaining components is the same as the calculation method of the synergistic dose range, and according to the combination relationship between the components of the combination drug, after obtaining the range of the antagonist amount of a certain target component drug, according to the above synergy
  • An algorithm with the same dose range yields a range of antagonist amounts for the remaining component drugs.
  • the processing method further comprises: calculating the actual dose-effect relationship curve within the range of the dose-effect curve a third dose range of a target component drug corresponding to the time; and outputting the third dose range as an additive dose range of a target component drug.
  • the additive dose range of a target component drug is the same as the calculation range of the synergistic dose range, and the intersection of the actual dose-effect curve and the dose-effect curve zone is the minimum of the target component drug when the combination drug is in the additive effect.
  • the dose and the maximum dose, the dose between the two doses, is the dose range for the additive effect.
  • the processing method further comprises: obtaining a joint relationship between a target component drug and the remaining component drugs in the combined drug; Calculate the additive dose range of the remaining components of the combination in combination; and output the additional dose range of the remaining components.
  • the additive dose range of the remaining component drugs is the same as the calculation method of the synergistic dose range, and is based on the combination relationship between the components of the combination drug, after obtaining the additive dose range of the above-mentioned target component drug According to the above algorithm with the same synergistic dose range, the additive dose range of the remaining component drugs is obtained.
  • the above-mentioned calculation of the additive dose range of a certain target component drug is in addition to the above-mentioned actual dose-effect relationship curve and dose-effect
  • the dose at the intersection of the curved band can be calculated by performing the following steps:
  • Bn+Bm) and the first combined dose expected additive effect curve Y"(Am+Bn) p(Bn+Bm);
  • Am+An) and the second combined dose expected additive effect curve Y"(Am+Bn) q(Bn+Bm);
  • the dose between the above combined dose Am 1 and the combined dose Am 2 is used as the dose range of the first component A when the additive effect is additive;
  • the dose range of the second component drug B when the combined drug efficacy is the additive effect is calculated.
  • the calculation method of the dose range between the components in the above additive effect is also applicable to three combinations of three or more components, and when the types of the combination are two, the above steps can be used to obtain a plurality of similarities.
  • the minimum and maximum values in the set were selected as the dose range of the additive effect of the two agents.
  • the additive effect dose range of the remaining components can be calculated based on the combined conditions. This method is more convenient when calculating the additive effect dose range.
  • the step of comparing the positional relationship between the actual dose-response relationship curve and the dose-effect curve includes: obtaining an expected phase of the corresponding combination drug in the range of the dose-effect curve at a specific combined dose The minimum and maximum values of the additive effect; the actual effect value of the corresponding combination drug on the actual dose-effect relationship curve at a specific combination dose; the minimum of the actual effect value and the expected additive effect is calculated.
  • a first ratio of values; a second ratio of the actual effect value to a maximum of the expected additive effect; the first ratio and the second ratio are labeled CI d1 and CI d2 , respectively; if CI d1 and CI d2 are both greater than 1, Then, it is determined that the actual dose-effect relationship curve is located above the dose-effect curve; if both CI d1 and CI d2 are less than 1, it is determined that the actual dose-effect relationship curve is located below the dose-effect curve; if any of CI d1 and CI d2 is greater than If it is equal to 1 or less than or equal to 1, it is determined that the actual dose-effect relationship curve is within the range of the dose-effect curve.
  • the above embodiment facilitates judging the positional relationship between the actual dose-effect relationship curve and the dose-effect curve at different effect value levels at any given dose.
  • the corresponding effect values on the actual dose-effect relationship curve are compared with the minimum and maximum values of the corresponding expected additive effects on the dose-effect curve, respectively, and the dose-based combination indices CI d1 and CI d2 are obtained.
  • CI d1 and CI d2 simultaneously greater than 1, it can be judged that the actual dose-effect relationship curve is above the dose-effect curve; CI d1 and CI d2 are simultaneously less than 1, and the actual dose-effect relationship curve can be judged in the dose-effect curve Above; and one of CI d1 and CI d2 is greater than or equal to 1, or one of CI d1 and CI d2 is less than or equal to 1, indicating that one of the actual effect values is on the dose-effect curve of the expected additive effect, Additive effect.
  • the processing method further comprises the step of outputting CI d1 and CI d2 .
  • This step facilitates the use of the actual combination of drugs, toxicology research and environmental assessment, according to the actual drug combination, the dose combination index.
  • the step of comparing the positional relationship between the actual dose-effect relationship curve and the dose-effect curve band may further include: obtaining a dose of a certain target component drug corresponding to the specific effect produced by the combination drug on the dose-effect curve band.
  • the fourth ratio; the third ratio and the fourth ratio are respectively labeled as CI e1 and CI e2 ; if both CI e1 and CI e2 are less than 1, it is determined that the actual dose-effect relationship curve is above the dose-effect curve; if CI e1 If CI e2 is greater than 1, it is determined that the actual dose-effect relationship curve is located below the dose-effect curve; if any of CI e1 and CI e2 is greater than or equal to 1 or less than or equal to 1, it is determined that the actual dose-effect relationship
  • the above examples facilitate comparison of the positional relationship between the actual dose-effect curve and the dose-effect curve in different dose ranges at any given level of efficacy.
  • a specific efficacy value such as ED 50
  • a vertical line parallel to the abscissa is used for the dose-effect curve and the actual dose-effect curve.
  • the abscissa values corresponding to the three points A, B and C are obtained, if they are 1.012, 1.321 and 1.450 respectively.
  • CI e1 and CI e2 are less than 1, it is determined that the actual dose-effect relationship curve is above the dose-effect curve; if CI e1 and CI e2 are greater than 1, it is determined that the actual dose-effect relationship curve is below the dose-effect curve If CI e1 or CI e2 is greater than or equal to 1, it is determined that the actual dose-effect relationship curve is within the range of the dose-effect curve.
  • the positional relationship comparison method of the above embodiment is based on the dose-effect curve, under the same dose condition or at a given efficacy level, based on the two effect values or two on the dose-effect curve with the expected additive effect.
  • the dose value can be used to more accurately quantify the efficacy of the combination according to the combined use index. For example, when CI e1 ⁇ 1 and CI e2 ⁇ 1, it is determined that the actual dose-effect relationship curve is located below the dose-effect curve, and the pharmacodynamic effects of the combination drug are synergistic.
  • the processing method further includes the step of outputting CI e1 and CI e2 .
  • the processing method further includes the step of outputting CI e1 and CI e2 .
  • the processing method of the drug efficacy according to the above embodiments can be implemented by means of software plus a necessary general hardware platform, and of course, by hardware. But in many cases the former is a better implementation.
  • the technical solution of the present application which is essential or contributes to the prior art, may be embodied in the form of a software product stored in a storage medium (such as ROM/RAM, disk,
  • the optical disc includes a number of instructions for causing a terminal device (which may be a mobile phone, a computer, a server, or a network device, etc.) to perform the methods described in various embodiments of the present application.
  • the processing device includes: a first acquisition module 10, a second acquisition module 30, a first comparison module 50, and a An output module 71, a second output module 73 and a third output module 75;
  • the first obtaining module 10 is configured to obtain a dose-effect curve of the expected additive effect of the combined drug, and the dose-effect curved band is surrounded by two outermost two of the plurality of equivalent dose-effect curves, each equivalent amount Effect curve refers to the drug of a certain target component in the combination drug.
  • the dose is the abscissa, and the curve is established by the equivalent conversion effect of the combination drug for each component drug as the ordinate; the equivalent exchange is equivalently exchanged according to the order of administration of each component in the combination drug. ;
  • the second obtaining module 30 is configured to obtain an actual dose-effect relationship curve formed by the actual effect value of the combined drug according to the dose change of a certain target drug in the combined drug;
  • a first comparison module 50 configured to compare a position relationship between the actual dose-effect relationship curve and the dose-effect curve
  • the first output module 71 is configured to output the pharmacodynamics of the combination drug as synergy when the actual dose-effect relationship curve is located above the dose-effect curve;
  • a second output module 73 configured to output the pharmacodynamic effect of the combination drug as an antagonist when the actual dose-effect relationship curve is located below the dose-effect curve;
  • the third output module 75 is configured to output the pharmacodynamic effects of the combination as the sum when the actual dose-effect relationship curve is within the range of the dose-effect curve.
  • the first comparison module is used to actually The dose-effect relationship curve is compared with the positional relationship of the dose-effect curve, and the comparison result is obtained. Finally, according to the difference of the comparison results, the different effects of the combination of the first output module, the second output module or the third output module are respectively selected. .
  • the combined dose-effect band can not only express the expected additive effect of the combination by a mathematical function, but also the dose-effect curve is in accordance with the dose-effect relationship of the drug and the pharmacodynamics of the multi-drug combination. charactermatic.
  • the dose-effect curve also comprehensively influences the effect of the order of action of the drug on the efficacy of the combination drug and the effect of the sequence of each component in the combination of the drug efficacy execution unit on the efficacy of the final combination drug. Therefore, by comparing the positional relationship between the dose-effect curve of the combination drug and the actual dose-effect relationship curve, not only the pharmacological effects of the combination drug can be accurately obtained, but also various indexes related to the combination drug can be obtained.
  • the expected additive effect of the combination drug is equivalently converted into the expected additive effect of each component drug. And then establish an equivalent dose-effect curve formed by the expected additive effect of each combination drug with the dose change of a certain target component drug, and then obtain the two outermost curved curves of the plurality of equivalent dose-effect curves a dose-effect curve with which the expected additive effect of the combination is obtained; at the same time, the actual dose-effect relationship of the actual effect value of the combination obtained with the dose of a target component in the combination is obtained in the second acquisition module After the curve; the first comparison module is executed to compare the positional relationship between the dose-effect curve and the actual dose-effect curve, and finally, according to the comparison result, the actual dose-effect curve is located above, below or within the range of the dose-effect curve, correspondingly
  • the first output module, the second output module, or the third output module respectively output the synergistic effects of the combination drugs as syn
  • the equivalent additive effect of the combination drug is equivalently converted into the equivalent dose-effect curve of each component drug, so that the combination drug is obtained.
  • the dose-effect curve of the expected additive effect is the same as the dose-effect curve of each component itself, since the additive effect is a zero interaction, when multiple drugs are simultaneously exposed to each of the drug efficacy units in the body tissue The order in which the effects of the drug work is random. Therefore, the expected additive effect of the combination drug is the sum of the effects of all the drug performance units, and the efficacy of a drug performance unit is exerted.
  • the order is that on the basis of the effect of the first component drug A, B exerts the effect of self-dose along the dose-effect curve of B itself; and the other drug-effect execution unit may exhibit the effect of the drug B in the second component. Based on this, A then exerts its own dose effect along the dose-effect curve along A itself.
  • the expected additive effect value is a range, that is, a set of numbers, and the two expected additive effect values are the boundary values of the set, which represent all
  • the execution unit is 100% Am ⁇ Bn and 100% Bn ⁇ Am
  • the intermediate value range is the sum of the cumulative effects of different ratios of Am ⁇ Bn and Bn ⁇ Am efficacy execution unit. It is expected that the additive effect value is in the range of the number set in accordance with the dose-effect curve relationship, rather than a straight line in the prior art.
  • the acquisition process of the dose-effect curve in the first acquisition module may be formed by establishing a plurality of equivalent dose-effect curves, and the establishment of the equivalent dose-effect curve may be implemented by an equivalent dose-effect curve building module.
  • the combination drug comprises a first component drug A and a second component drug B
  • the processing device further comprises an equivalent dose effect curve establishing module, wherein the equivalent dose effect curve establishing module is used in the first acquiring module A plurality of equivalent dose-effect curves are established before the step of obtaining the dose-effect curve of the expected additive effect of the combination;
  • the first conversion unit is used to convert the effect value g(Bn+Bm) into the expected additive effect value Y(Am+Bn) of the combination
  • the first curve establishing unit is used to establish the expected addition of the combination drug.
  • the second calculation unit is used to calculate the combined dose Am of the first component drug A and the equivalent dose
  • the sixth search unit is used Find or calculate the dose of the first
  • the equivalent dose-effect curve establishing module in the above embodiment obtains the dose-effect relationship curves of the two component drugs by the first acquiring unit and the second acquiring unit, and then executes the first searching unit, the second searching unit, and the first calculating unit. Equivalently converting the effect produced by the combined dose of the first component A to the second component B, and then performing the third finding unit to find the expected additive effect of the combination to be equivalently converted into the second component
  • the dose value of B and the corresponding effect value; then the dose of the second component B and the corresponding effect value are converted into the expected additive effect of the combination by the first conversion unit, and finally passed
  • the first component drug A and the second component drug B do not specifically refer to two drugs, but may be continuously updated depending on the type and order of the components. Therefore, in the above-mentioned equivalent dose-effect curve establishing module, the dose-effect relationship curve information of the first component drug A and the second component drug B is also updated at any time depending on the type and order of the drug. For example, when the second component drug B is updated to the first component drug A, the above-mentioned equivalent dose-effect curve establishing module establishes the equivalent of the pharmacodynamic equivalent of the combined drug to the first component drug A. Dose curve.
  • the first obtaining module respectively establishes each equivalent dose-effect curve by the equivalent dose-effect curve establishing module, and the first acquiring module obtains the joint by obtaining the two outermost two equivalent dose-effect curves of all the equivalent dose-effect curves A dose-effect curve of the expected additive effect of the drug.
  • the processing device further includes: a first calculating module and a fourth output module; wherein the first calculating module is configured to calculate the actual amount after the first output module outputs the synergistic effects of the combination medicine a first dose range of a target component drug corresponding to the relationship curve above the dose-effect curve; and a fourth output module for outputting the first dose range as a synergistic dose range for a target component drug .
  • the first calculation module is capable of calculating a dose of a target component drug at an intersection of a practical dose-effect curve and a dose-effect curve according to a function relationship between the actual dose-effect relationship curve and the dose-effect curve, and further The dose can be calculated to be the first dose range corresponding to the synergistic effect above the intersection.
  • the processing device further includes: a third acquiring module, configured to acquire a target in the combination after the fourth output module outputs the first dose range as a synergistic dose range of the target component a combination relationship between the component drug and the remaining component drugs; a second calculation module for calculating a synergistic dose range of the remaining components of the combination drug under the combined condition according to the combination relationship; and a fifth output module, A synergistic dose range for outputting the remaining component drugs.
  • a third acquiring module configured to acquire a target in the combination after the fourth output module outputs the first dose range as a synergistic dose range of the target component a combination relationship between the component drug and the remaining component drugs
  • a second calculation module for calculating a synergistic dose range of the remaining components of the combination drug under the combined condition according to the combination relationship
  • a fifth output module A synergistic dose range for outputting the remaining component drugs.
  • A is the target component drug
  • the pharmacodynamic effect of the combination drug can be calculated.
  • the synergistic dosage range of the remaining component drugs can also be obtained according to the specific combination relationship. For example, when A and B are combined, in which A is combined with a different concentration ( ⁇ g/ml) of B drug ⁇ g/ml at a fixed concentration of 1 ng/ml, the synergistic dose of the target drug B is calculated. In the range, the synergistic dose range of the A-component drug is the combined fixed dose.
  • the synergistic dosage range of each component is combined according to the combined relationship, and the synergistic dose range of the synergistic drug can be obtained.
  • the processing device further includes: a third calculating module, configured to output, after the second output module, the pharmacodynamic effect of the combination drug as an antagonist, and calculate the actual dose-effect relationship curve under the dose-effect curve Corresponding a second dose range of a certain target component drug, and a sixth output module for outputting the second dose range as an antagonist amount range of a certain target component drug.
  • a third calculating module configured to output, after the second output module, the pharmacodynamic effect of the combination drug as an antagonist, and calculate the actual dose-effect relationship curve under the dose-effect curve Corresponding a second dose range of a certain target component drug
  • a sixth output module for outputting the second dose range as an antagonist amount range of a certain target component drug.
  • the third calculating module calculates a second dose range of a certain target component drug corresponding to the actual dose-effect relationship curve under the dose-effect curve, and may also be located in the dose-effect curve according to the actual dose-effect relationship curve.
  • the dose corresponding to the position at the intersection is then taken to determine the range of doses under which the effect is below the dose effect, i.e., the range of antagonist amounts for a particular component of the drug.
  • the processing device further includes: a fourth acquiring module, configured to obtain a target group in the combination after the sixth output module outputs the second dose range as an antagonist amount range of a target component drug a combination relationship between the divided drug and the remaining component drugs; a fourth calculating module for calculating the range of the antagonist amount of the remaining component drugs in the combined drug according to the combined relationship; and the seventh output module The range of the amount of the antagonist for outputting the remaining component drugs.
  • a fourth acquiring module configured to obtain a target group in the combination after the sixth output module outputs the second dose range as an antagonist amount range of a target component drug a combination relationship between the divided drug and the remaining component drugs
  • a fourth calculating module for calculating the range of the antagonist amount of the remaining component drugs in the combined drug according to the combined relationship
  • the seventh output module The range of the amount of the antagonist for outputting the remaining component drugs.
  • the method for calculating the range of the antagonist amount of the remaining components by the fourth obtaining module and the fourth calculating module is the same as the method for calculating the synergistic dose range, and is based on the joint relationship between the components in the combined drug.
  • the range of the antagonist amount of a certain target component drug is obtained according to the same algorithm of the above synergistic dose range.
  • the processing device further includes: a fifth calculating module, configured to calculate the actual dose-effect relationship curve after the third output module outputs the combined effects of the drugs a third dose range of a target component drug corresponding to the range of the effect band; and an eighth output module for outputting the third dose range as an additive dose range of a target component drug.
  • a fifth calculating module configured to calculate the actual dose-effect relationship curve after the third output module outputs the combined effects of the drugs a third dose range of a target component drug corresponding to the range of the effect band
  • an eighth output module for outputting the third dose range as an additive dose range of a target component drug.
  • the fifth calculation module calculates the additive dose range of a certain target component drug in the same manner as the calculation of the range of the synergistic dose range, and the intersection point between the actual dose-effect curve and the dose-effect curve band is the additive effect. At the time of the minimum dose and the maximum dose of the target component, the dose between the two doses is the dose range of the additive effect.
  • the processing device further includes: a fifth obtaining module, configured to: after the eighth output module outputs the third dose range as a dose range of a target component drug, Obtain a target group in the combination a combination relationship between the divided drug and the remaining component drugs; a sixth calculating module for calculating a combined dose range of the remaining components of the combined drug under the combined condition according to the combined relationship; and a ninth output module, Used to output the additive dose range of the remaining component drugs.
  • a fifth obtaining module configured to: after the eighth output module outputs the third dose range as a dose range of a target component drug, Obtain a target group in the combination a combination relationship between the divided drug and the remaining component drugs
  • a sixth calculating module for calculating a combined dose range of the remaining components of the combined drug under the combined condition according to the combined relationship
  • a ninth output module Used to output the additive dose range of the remaining component drugs.
  • the fifth obtaining module and the sixth calculating module calculate the added dose range of the remaining component drugs in the same manner as the method for calculating the synergistic dose range, which are obtained according to the joint relationship between the components in the combined drug. After the above-mentioned additive dose range of a certain target component drug, the added dose range of the remaining component drugs is obtained according to the same algorithm of the above synergistic dose range.
  • the first comparison module includes: a first acquisition sub-module, configured to obtain a minimum expected anti-additive effect of the corresponding combination drug in the range of the effective effect band under a specific combined dose of a certain target component drug Value and maximum value; a second acquisition sub-module for obtaining the actual effect value of the corresponding combination drug on the actual dose-effect relationship curve of a certain target component drug; the first calculation sub-module, a first ratio for calculating a minimum value of the actual effect value and the expected additive effect; a second calculation sub-module for calculating a second ratio of the actual effect value to the maximum value of the expected additive effect; the first marker sub-module, The first ratio and the second ratio are respectively labeled as CI d1 and CI d2 ; the first determining sub-module is configured to determine that the actual dose-effect relationship curve is above the dose-effect curve when both CI d1 and CI d2 are greater than one a second determining sub-module, configured to determine that the actual dose
  • the above embodiment facilitates judging the positional relationship between the actual dose-effect relationship curve and the dose-effect curve at different effect value levels at any given dose.
  • the corresponding effect values on the actual dose-effect relationship curve are compared with the minimum and maximum values of the corresponding expected additive effects on the dose-effect curve, respectively, and the dose-based combination indices CI d1 and CI d2 are obtained.
  • CI d1 and CI d2 simultaneously greater than 1, it can be judged that the actual dose-effect relationship curve is above the dose-effect curve; CI d1 and CI d2 are simultaneously less than 1, and the actual dose-effect relationship curve can be judged in the dose-effect curve Above; and one of CI d1 and CI d2 is greater than or equal to 1, or one of CI d1 and CI d2 is less than or equal to 1, indicating that one of the actual effect values is on the dose-effect curve of the expected additive effect, Additive effect.
  • processing means further comprises an eleventh output module for marking the first sub-module of the first ratio and the second ratio are labeled CI d1 and CI d2, and outputs CI d1 CI d2.
  • the module can be output according to the needs of the specific dosage of the combined dose in practical applications.
  • the first comparison module includes: a third obtaining sub-module, configured to obtain a minimum value and a maximum value of a dose of a certain target component drug corresponding to the specific effect produced by the combination drug on the dose-effect curve;
  • the fourth acquisition sub-module is configured to obtain the actual combined dose required for the combined effect to produce a specific effect on the actual dose-effect relationship curve;
  • the dose-effect relationship curve is located below the dose-effect curve; and the sixth determining sub-module is configured to determine that the actual dose-effect relationship curve is located in the dose-effect curve when any one of CI d1 and CI d2 is greater than or equal to 1 or less than or equal to In the range.
  • the above examples facilitate comparison of the positional relationship between the actual dose-effect curve and the dose-effect curve in different dose ranges at any given level of efficacy.
  • a specific efficacy value such as ED 50
  • a vertical line parallel to the abscissa is used for the dose-effect curve and the actual dose-effect curve.
  • the abscissa values corresponding to the three points A, B and C are obtained, if they are 1.012, 1.321 and 1.450 respectively.
  • CI e1 and CI e2 are less than 1, it is determined that the actual dose-effect relationship curve is above the dose-effect curve; if CI e1 and CI e2 are greater than 1, it is determined that the actual dose-effect relationship curve is below the dose-effect curve If CI e1 or CI e2 is greater than or equal to 1, it is determined that the actual dose-effect relationship curve is within the range of the dose-effect curve.
  • the positional relationship comparison method of the above embodiment is based on the dose-effect curve, under the same dose condition or at a given efficacy level, based on the two effect values or two on the dose-effect curve with the expected additive effect.
  • the dose value can be used to more accurately quantify the efficacy of the combination according to the combined use index. For example, when CI e1 ⁇ 1 and CI e2 ⁇ 1, it is determined that the actual dose-effect relationship curve is located below the dose-effect curve, and the pharmacodynamic effects of the combination drug are synergistic.
  • the processing device further includes a twelfth output module, configured to output the CI d1 and CI after the second marking submodule marks the third ratio and the fourth ratio as CI e1 and CI e2 respectively D2 .
  • the output module can meet the needs of the effect sharing index in practical applications.
  • the modules provided in this embodiment are the same as the methods used in the corresponding steps of the method embodiment, and the application scenarios may be the same.
  • the solution involved in the above module may not be limited to the content and scenario in the foregoing embodiment, and the foregoing module may be run on a computer terminal or a mobile terminal, and may be implemented by software or hardware.
  • the embodiment of the present application may further provide a computer terminal, which may be any one of the computer terminal groups.
  • a computer terminal which may be any one of the computer terminal groups.
  • the foregoing computer terminal may also be replaced with a terminal device such as a mobile terminal.
  • the computer terminal can include: one or more processors, memory, and transmission devices.
  • the memory can be used to store the software program and the module, such as the combined drug efficacy processing method and the program instruction/module corresponding to the device in the embodiment of the present application, and the processor executes the software program and the module stored in the memory, thereby executing each The functional application and data processing, that is, the above-mentioned combined drug efficacy treatment method is realized.
  • the memory may include a high speed random access memory, and may also include non-volatile memory such as one or more magnetic storage devices, flash memory, or other non-volatile solid state memory.
  • the memory can further include memory remotely located relative to the processor, which can be connected to a terminal via a network. Examples of such networks include, but are not limited to, the Internet, intranets, local area networks, mobile communication networks, and combinations thereof.
  • the processor can call the memory stored information and the application by the transmission device to perform the following steps: obtaining a dose-effect curve of the expected additive effect of the combination drug, and the dose-effect curve is the outermost periphery of the plurality of equivalent dose-effect curves Two of each, each
  • the equivalent dose-effect curve refers to the curve established by taking the dose of a certain target component in the combination as the abscissa and the expected additive effect obtained by the equivalent exchange of the combination into each component as the ordinate.
  • Equivalent exchange is carried out according to the order of administration of each component in the obtained combination drug; the actual dose-effect relationship of the actual effect value of the combination drug with the dose change of a certain target drug in the combination drug is obtained; Curve; compare the positional relationship between the actual dose-effect relationship curve and the dose-effect curve, and when the actual dose-effect relationship curve is above the dose-effect curve, the drug effect output of the combination drug is synergistic; when the actual dose-effect relationship curve is located When the dose-effect curve is below, the pharmacodynamic output of the combination drug is antagonized; when the actual dose-effect curve is within the range of the dose-effect curve, the drug effect output of the combination drug is added.
  • the combination drug comprises a first component drug A and a second component drug B
  • the above treatment method further comprises establishing a plurality of equivalents before the step of obtaining a dose-effect curve band of the expected additive effect of the combination drug
  • the dose sum of the combined dose n and the equivalent dose Bm is combined; the dose of the second
  • the above treatment method of the present application compares the actual dose-response curve of the combination drug based on the dose-effect curve based on the expected additive effect of the combination drug, and then judges the relationship by the positional relationship between the actual dose-effect curve and the dose-effect curve band.
  • the efficacy of medication Since the dose-effect curve is in accordance with the dose-effect relationship of the drug and the pharmacodynamic basic characteristics of the drug combination, the pharmacodynamic treatment method of the embodiment combines the difference in the order of administration of the plurality of drugs in combination and the difference in the dose-effect relationship of the different drugs.
  • the effect of the pharmacodynamics of the combination drug can not only achieve the detection of the efficacy of multiple (two or more) drugs, but also achieve quantitative detection.
  • the treatment method not only solves the problem that the efficacy of the multi-drug combination in the prior art cannot be accurately detected, but also the efficacy of the detected combination drug can be widely applied in the research and development, toxicology research and environmental evaluation of the compound medicine. .
  • Embodiments of the present application also provide a storage medium.
  • the foregoing storage medium may be used to save the program code executed by the combined medicine efficacy processing method provided by the foregoing embodiment.
  • the foregoing storage medium may be located in any one of the computer terminal groups in the computer network, or in any one of the mobile terminal groups.
  • the storage medium is arranged to store program code for performing the following steps:
  • the dose-effect curve is surrounded by the outermost two of the plurality of equivalent dose-effect curves, and each equivalent dose-effect curve refers to a certain combination of drugs
  • the dose of a target component drug is the abscissa, and the curve is established by the equivalent conversion effect of the combination drug for each component drug as the ordinate; the equivalent exchange is according to the groups in the obtained combination drug.
  • Equivalent exchange of the drug-using sequence obtaining the actual dose-effect relationship curve of the actual effect value of the drug combination with the dose change of a certain target drug in the combination drug; comparing the actual dose-effect relationship curve with the dose-effect curve
  • the positional relationship, and when the actual dose-response relationship curve is located above the dose-effect curve, the drug effect output of the combination drug is synergistic; when the actual dose-effect relationship curve is located below the dose-effect curve, the drug of the combination drug is used.
  • the effect output is antagonistic; when the actual dose-effect relationship curve is within the range of the dose-effect curve, the drug effect output of the combination drug is added.
  • the corresponding effect value g(Bn+Bm) convert the effect value g(Bn+Bm) into the expected additive effect value Y(Am+Bn
  • the dose-effect curve based on the expected additive effect of the combination drug is compared with the actual dose-effect curve of the combination drug, and then the positional relationship between the actual dose-effect curve and the dose-effect curve band is adopted.
  • the pharmacodynamic treatment method of the embodiment combines the difference in the order of administration of the plurality of drugs in combination and the difference in the dose-effect relationship of the different drugs.
  • the effect of the pharmacodynamics of the combination drug can not only achieve the detection of the efficacy of multiple (two or more) drugs, but also achieve quantitative detection.
  • the treatment method not only solves the problem that the efficacy of the multi-drug combination in the prior art cannot be accurately detected, but also the efficacy of the detected combination drug can be widely applied in the research and development, toxicology research and environmental evaluation of the compound medicine. .
  • the disclosed technical contents may be implemented in other manners.
  • the device embodiments described above are merely illustrative.
  • the division of the unit is only a logical function division.
  • multiple units or components may be combined or may be Integrate into another system, or some features can be ignored or not executed.
  • the mutual coupling or direct coupling or communication connection shown or discussed may be an indirect coupling or communication connection through some interface, unit or module, and may be electrical or otherwise.
  • the units described as separate components may or may not be physically separated, and the components displayed as units may be physical units or may not be physical units, that is, may be located in one place, or may be distributed to multiple network units. on. Some or all of the units may be selected according to actual needs to achieve the purpose of the solution of the embodiment.
  • each functional unit in each embodiment of the present application may be integrated into one processing unit, or each unit may exist physically separately, or two or more units may be integrated into one unit.
  • the above integrated unit can be implemented in the form of hardware or in the form of a software functional unit.
  • the integrated unit if implemented in the form of a software functional unit and sold or used as a standalone product, may be stored in a computer readable storage medium.
  • a computer readable storage medium A number of instructions are included to cause a computer device (which may be a personal computer, server or network device, etc.) to perform all or part of the steps of the methods described in various embodiments of the present application.
  • the foregoing storage medium includes: a U disk, a Read-Only Memory (ROM), a Random Access Memory (RAM), a removable hard disk, a magnetic disk, or an optical disk, and the like. .
  • Example 1 Treatment method for the efficacy of two drugs
  • Nitrate is an anti-infective drug. It has been found to have targeted anti-cancer activity in recent years. SFDA has approved the entry into clinical trials; paclitaxel (TX) is a commonly used anticancer drug in clinical practice. Combined with NX/TX, MTT assay was used to detect the growth of HepG2 in human hepatoma cells. Describe the methods for quantitatively processing the synergistic/additive/antagonistic related indicators to provide reference for the development of new anticancer compounds.
  • Step 1 Prepare a dose-effect relationship table for each member of each single drug and combination group, and fit the respective dose-effect relationship curve equations.
  • the dose-effect relationship data of nitro compound (NX) and paclitaxel (TX) and single drug, NX+TX combined in a fixed ratio (1/1, ⁇ g/ml/ng/ml), fixed concentration of TX (2ng/ml) ) + dose-response relationship data for different concentrations of NX, see Table 1.
  • a dose-response graph of the drug NX in the drug NX and drug TX alone, drug combination groups is plotted, as shown in FIGS. 3A, 3B, 3C, and 3D.
  • NX:Y (15.8595-94.9017)/ ⁇ 1+(X/1.7190) ⁇ 2.4490 ⁇ +94.9017, and the actual dose-effect relationship curve is shown in Fig. 3C.
  • NX:Y (7.294-94.22)/ ⁇ 1+(X/1.569 ⁇ 3.1080 ⁇ +94.22 in the fixed concentration group of TX, the actual dose-effect relationship curve is shown in Fig. 3D;
  • Step 2 The dose is sequentially exchanged, and the dose-effect relationship data constituting the expected additive effect curve under the combined conditions are calculated.
  • Direct calculation method evaluate several existing combined dose points.
  • the dose levels of NX in the combined group are plotted on the abscissa and the expected additive effect values are plotted on the ordinate to form a dose-effect curve of the expected equivalent additive effect.
  • the actual effect curve of the combined group is made on the graph, as shown in FIG. It can be seen from Fig. 4 that the area enclosed by the two curves of the thick line is the dose-effect curve of the expected addition effect, and the curve of the thin line is the actual dose-effect relationship curve of the combined group, which is related to the additive effect zone.
  • Convergence That is, in the combined dose range, there are synergistic parts, additive parts, and antagonistic parts.
  • each column indicates: (3) column: from table 2; (4) column: from table 3; (5) column: from table 1; (6) column: (5) column data / (3) column data; (7) Column: (5) column data / (4) column data; (8) column: standard see CId calculation.
  • the direct calculation method can roughly judge the state of synergy, addition and antagonism. It is possible to judge the dose level of the existing combination group, but the difference between each dose level on the abscissa is large, and the dose range of various pharmacodynamic effects can only be estimated, and the dose of each part cannot be accurately determined. It is possible to judge whether or not to perform an accurate calculation. If it is necessary to accurately calculate the dose range of various pharmacodynamic effects, it is necessary to insert several intermediate dose values between each dose level, and calculate the expected additive effect after sequential dose conversion according to the established dose-effect relationship function. Value, then perform function fitting.
  • the first step is to use NX as the target drug, and after the equivalent dose is exchanged for TX, the equivalent dose is combined, and the expected additive effect value is calculated by using the NX's dose-effect curve equation, see (3) in Table 4, 4), (5), (6) column data.
  • TX is used as the target drug.
  • the equivalent dose is exchanged for NX, the equivalent dose is combined, and the expected additive effect value is calculated by using the dose-effect curve equation of TX alone. See (7) of Table 6 ( 8), (9), (10) column data.
  • Table 6 Calculation table of the expected additive effect after the nitrate-based compound (NX) + paclitaxel (TX) was combined at a fixed ratio and the equivalent dose was exchanged for the target drug of TX.
  • Step 3 reconstruct the dose-effect curve and the fit curve equation
  • the expected additive effect is formed by plotting the expected additive effect value and the fitted actual effect value [(6) column, (10) column] as the ordinate.
  • the dose-effect curve is made on the graph, as shown in FIG.
  • the dose-effect equation was fitted to the expected additive effect value of the NX dose in the combined group and NX as the target drug.
  • the NX dose and TX are the expected additive effect values of the target drug, and the two effect curves are obtained by the dose-effect equation, and the equivalent dose-effect curves of the dose-effect curve are obtained.
  • the equations are:
  • TX (8.534-93.93) / ⁇ 1 + (X / 1.439) ⁇ 2.478 ⁇ + 93.93;
  • Step 4 compares the positional relationship between the dose-effect curve and the actual dose-effect curve of the expected additive effect of the combined group, and calculates the relevant index.
  • the NX dose limit for the additive effect is 0.6344 and 0.9359 ⁇ g/ml. Depending on the combination of NX and TX (1:1), the dose range of the TX additive effect is easily obtained. NX and TX are within the common effect range,
  • Antagonistic effect dose range (NX+TX): (0.9359 + 0.9359, 6 + 6) ⁇ g / ml + ng / ml.
  • the range of additive effects in the actual effect dose-effect curve of the combined group is: 22.101% to 30.4090%.
  • NX and TX are outside the common effect range, and there is an additive effect point (NX+TX: 11.2124+11.2124, ⁇ g/ml+ng/m). It can be seen that the combined dose point is 8+8 ( ⁇ g/ml). +ng/ml) below this point, for antagonism; 16+16 ( ⁇ g/ml+ng/ml), above which is synergy.
  • the expected additive effect values for the dose point 0.5 + 0.5 were 11.5 and 14.2, respectively, and the actual observed value was 19.7 (Table 4).
  • the expected additive effect values for the dose point 1+1 were 48.7 and 33.2, respectively, and the actual observed value was 23.8.
  • the dose point 2+2 ( ⁇ g/ml+ng/ml), 4+4 ( ⁇ g/ml+ng/ml), CI d1 and CI d2 were all ⁇ 1, antagonism.
  • the calculation of dose points 8+8 ( ⁇ g/ml+ng/ml) and 16+16 ( ⁇ g/ml+ng/ml) CI d is omitted.
  • the dose range point (NX+TX) of the expected additive effect is 1.0196+1.0196 ( ⁇ g/ml+ng/ml) and 1.4059+1.4059 ( ⁇ g/ml+ng/ml), the actual effect
  • the dose point (NX + TX) is 1.5370 + 1.5370 ( ⁇ g / ml + ng / ml), located below the dose-effect curve.
  • Step 1 Prepare a dose-effect relationship table for each dose level of each single drug and combination group, and fit the respective dose-effect relationship curve equations.
  • NX nitrate-based compound
  • TX paclitaxel
  • a dose-response graph of the drug NX in the drug NX and drug TX alone, drug combination groups is plotted, as shown in FIGS. 3A, 3B, and 3D.
  • the logistic program is used to fit the respective dose-effect relationship equations, respectively:
  • Step 2 The dose is sequentially exchanged, and the respective dose-effect relationship data constituting the expected additive effect curve band under the combined conditions are calculated.
  • Accurate calculation method Calculate the combined dose value after the equivalent dose conversion in the fixed dose of 2ng/ml of TX. In order to improve the fitting accuracy of the expected additive effect curve, several intermediate dose values can be inserted between each combined dose. The data of this group is set with 4 interpolation values per dose interval, such as 0.5+0.5 and 1+1. Between, it increased by 0.6+0.6, 0.7+0.7, 0.8+0.8, 0.9+0.9 and so on.
  • the first step is to use NX as the target drug.
  • the equivalent dose is exchanged for TX, the equivalent dose is combined, and the expected additive effect value is calculated by using the NX curve of the effect curve. See (3) of Table 7 ( 4), (5), (6) column data.
  • Table 7 is a table for calculating the expected additive effect after the nitrate-hydroxy compound (NX) + paclitaxel (TX) is used in a fixed ratio and the equivalent dose is exchanged sequentially with NX as the target drug.
  • TX is used as the target drug.
  • the equivalent dose is exchanged for NX, the equivalent dose is combined, and the expected additive effect value is calculated by using the dose-effect curve equation of TX alone. See (7) of Table 8 ( 8), (9), (10) column data.
  • Table 8 shows the calculation of the expected additive effect after the fixed concentration of paclitaxel (TX) + nitrate compound (NX) is used in different proportions, and the equivalent dose is exchanged for the sequential treatment of TX.
  • Step 3 reconstruct the dose-effect curve and the fit curve equation
  • the dose-effect equation was fitted to the expected additive effect value of the NX dose in the combined group and NX as the target drug.
  • the expected additive effect value of NX dose and TX as the target drug was fitted by the dose-effect equation, and the two equivalent dose-effect curves surrounding the expected additive effect volume curve were obtained.
  • the curve equations were:
  • TX (9.95-94.91) / ⁇ 1 + (X / 1.976) ⁇ 2.41 ⁇ + 94.91.
  • Step 4 compares the positional relationship between the expected additive effect volume and the actual dose-effect curve of the combined group, and calculates the relevant indicators.
  • the NX dose limit for the additive effect is 2.1229 to 4.5777 ⁇ g/ml. Depending on the combination of NX and TX (fixed dose 2 ng/ml), the dose range of the TX additive effect is easily obtained. NX and TX are within the common effect range,
  • Antagonistic effect dose range (NX+TX): (4.5777 + 2, 6 + 2) ⁇ g / ml + ng / ml.
  • the range of the additive effect in the actual effect dose-effect curve of the combined group is 69.7986% to 91.2101%.
  • the expected additive effect value of the combined dose point 16+2 ( ⁇ g/ml+ng/ml) was 94.1563, while the actual observed value was 96.1, which was synergistic.
  • Example 2 Method for detecting efficacy of three drugs
  • chemotherapeutic drugs in the treatment of lung cancer.
  • the chemotherapeutic drugs in these programs mainly include the following: Topoisomerase inhibitors, microtubule inhibitors, metabolic inhibitors, alkylating agents from the class of chemotherapeutic drugs Wait for four categories. Select one representative drug from these four drugs, which are etoposide (A), vincristine (B), 5-fluorouracil (C), doxorubicin (D), or any combination of three.
  • MTT assay was used to detect the inhibitory effect on the growth of human lung cancer cell line H460.
  • the three regimens were A+B+C, A+B+D, A+C+D, B+C+D, etc., and their synergistic, additive and antagonistic effects were quantitatively evaluated.
  • Step 1 Prepare a dose-effect relationship table for each dose level of each single drug and combination group, and fit the respective dose-effect relationship curve equations.
  • A: B: C 12.5: 2:45 ( ⁇ g / ml + ⁇ g / ml + The dose-effect relationship data of ⁇ g/ml) is shown in Table 9 and Table 10.
  • Table 9 is a table of dose-effect relationship data for etoposide (A), vincristine (B) and 5-fluorouracil (C).
  • Table 10 is a dose-effect relationship data table for the combination of etoposide (A), vincristine (B) and 5-fluorouracil (C).
  • the logistic program is used to fit the respective dose-effect relationship equations, respectively:
  • Step 2 The dose is sequentially exchanged, and the respective dose-effect relationship data constituting the expected additive effect curve band under the combined conditions are calculated.
  • Etoposide (A), vincristine (B) and 5-fluorouracil (C) were calculated, and the combined dose values were sequentially performed after equivalent dose exchange under fixed ratio conditions.
  • the function value representing the unit in the number set shall be arranged from low (high) to high (high).
  • the expected additive effect values for the combination of A, B and C are (A+B)+C, (A+C)+B, and (B+C)+A. A collection of values to the highest value.
  • the first step take A as the target drug, convert B to the equivalent dose (A b ), combine the equivalent dose (A+A b ), and calculate the expected additive effect value by using the dose-effect curve equation of A alone. See Tables 3 (3), (4), (5), and (6) for column data.
  • Table 11 is a table for calculating the expected additive effect after a combination of etoposide (A) and vincristine (B) in a fixed ratio and an equivalent dose exchange of etoposide (A) as a target drug.
  • B is the target drug
  • A is equivalently exchanged (B a )
  • the equivalent dose (B+B a ) is combined, and the expected additive effect value is calculated by using the dose-effect curve equation of B alone. See Tables 7 (7), (8), (9), and (10) for column data.
  • Table 12 is a table for calculating the expected additive effect after a combination of etoposide (A) and vincristine (B) in a fixed ratio and sequential conversion of vincristine (B) as a target drug.
  • (A+B) (A+A b ) is the target drug, and C is equivalently exchanged (A c ), and the equivalent dose [(A+A b )+A c ] is combined.
  • (A+B) (B+B a ) is the target drug, and C is equivalent dose exchange (B c ), and the equivalent dose [(B+B a )+B c ] is combined.
  • the expected additive effect value is calculated by using the B dose-effect curve equation alone, as shown in the data of columns (15), (16), (17), and (18) in Table 14.
  • Table 15 is a table for calculating the expected additive effect after the combination of etoposide and vincristine (A+B) and 5-fluorouracil (C) in a fixed ratio and C for the equivalent dose of the target drug.
  • Table 16 is a table for calculating the expected additive effect after the combination of etoposide and vincristine (A+B) and 5-fluorouracil (C) in a fixed ratio and C for the equivalent dose of the target drug.
  • the first step take A as the target drug, convert C to the equivalent dose (A C ), combine the equivalent dose (A+A C ), and calculate the expected additive effect value by using the dose-effect curve equation of A alone.
  • (A+C) (A+A c ) is the target drug, and B is equivalent dose exchange (A b ), and the equivalent dose [(A+A c )+A b ] is combined. Calculate the expected additive effect value by using the A dose-effect curve equation alone.
  • (A+C) (C+C a ) is the target drug
  • B is equivalent dose exchange (C b )
  • the equivalent dose [(C+C a )+C b ] is combined. Calculate the expected additive effect value by using the C dose curve equation alone.
  • the first step take B as the target drug, convert C to the equivalent dose (B C ), combine the equivalent dose (B+B C ), and calculate the expected additive effect value by using the dose-effect curve equation of B alone.
  • (B+C) (B+B c ) is the target drug, and A is equivalently exchanged (B a ), and the equivalent dose [(B+B c )+B a ] is combined. Calculate the expected additive effect value by using the B dose-effect curve equation alone.
  • (B+C) (C+C b ) is the target drug, and A is equivalently exchanged (C a ), and the equivalent dose [(C+C b )+C a ] is combined. Calculate the expected additive effect value by using the C dose curve equation alone.
  • Step 3 reconstruct the dose-effect curve and the fit curve equation
  • the expected additive effect values of the three (A+B)+C, (A+C)+B, (B+C)+A combinations are taken as the abscissa for each dose level of the etoposide (A) in the combined group.
  • the data is plotted on the ordinate and 12 dose-effect curves are made (3 of which are the same, so 9 are shown).
  • the outermost curve is used as the boundary of the dose-effect curved band, as shown in Fig. 9A.
  • Step 4 compares the positional relationship between the expected additive effect volume and the actual dose-effect curve of the combined group, and calculates the relevant indicators.
  • Etoposide (A), vincristine (B) and 5-fluorouracil (C) in combination (A+B+C) at a fixed ratio of A:B:C 12.5:2:45 ( ⁇ g/ml+ ⁇ g/ Ml + ⁇ g / ml) of the three drugs in combination, within the common effect range,
  • Antagonistic effect dose range (A+B+C):
  • the second part is the quantitative calculation of synergy, addition and antagonism of several other combinations of three drugs, including:
  • the calculation step is the same as the calculation of the first part A+B+C (the calculation process is omitted).
  • the main results are as follows:
  • A The dose-effect curve and the actual dose-effect curve of the expected additive effect of the C:D combination group reconstruction, as shown in Fig. 11.

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Abstract

一种联用药药效的处理方法和处理装置。该处理方法包括：获取联用药的预期相加效应的量效曲带(S202)；获取联用药的实际效应值随联用药中的某一目标组分药的剂量变化形成的实际量效关系曲线(S204)；比较实际量效关系曲线与量效曲带的位置关系(S206)，以及当实际量效关系曲线位于量效曲带的上方时将联用药的药效输出为协同；当实际量效关系曲线位于量效曲带的下方时将联用药的药效输出为拮抗；当实际量效关系曲线位于量效曲带范围内时将联用药的药效输出为相加(S208)。该处理方法既解决了现有技术中多药联用时药效无法准确检测的问题，又能广泛应用于复方药的研发、毒理学研究、联合用药的药效与安全评价以及环境评价中。

Description

联用药药效的处理方法和处理装置 技术领域
本发明涉及生物医药领域，具体而言，涉及一种联用药药效的处理方法和处理装置。
背景技术
当前新药研发基本路径是针对某个疾病相关靶点，进行候选化合物的筛选和先导物的优化，进而进行成药性研究、临床前评价和临床实验后，方可批准上市。这种基于“单靶标，单疾病，单药物”的研究模式，特别是研发针对单一靶点的单一结构化合物药物，在治疗用途方面的出路愈来愈困难。许多难治性重大疾病的病因通常为多靶点、多环节，需针对多个环节方能奏效，而发展针对多个环节的单一结构的化合物新药，几乎是很难完成的任务。从解决问题的可行性和实际效果，给予患者联合用药或者研发新复方药物，才是疾病治疗和新药研发的宽阔路径。
而且，在现代医疗实践中也很少使用单一药物，常需要多药联合应用，少则2～3种，多则7～8种，甚至10多种。药物联合应用是对疾病最有效的治疗手段之一。中国传统医学中，多种动植物或矿物成分的联合使用，或者组成的固定方剂更是常见。多药联合应用的动因包括：对疾病的治疗，常需要针对多个环节或者针对多个靶点；患者常有多种疾病；任何疾病的治疗，需要对因治疗和对症治疗；任何药物的适应症和治疗窗口是有限的，且均有不同性质和不同程度的毒副作用。因此，联合用药的目的是获得最大的治疗效果以及最大程度地减轻毒副作用。对于一些严重疾病的治疗，如恶性肿瘤、感染性疾病、心脑血管疾病等，药物联用的治疗效果是非常显著的。在新药研发中，对各类型新药复方制剂的研发，实际上是将发挥最优治疗用途的多种药物联合应用，进行最大合理性的固定化。
然而，多种药物联合应用时，药物之间发生相互作用的层面包括以下几种：1)药物理化性质的相互影响，是指药物在配伍和合用时，理化性质方面发生的改变。国家药物主管部门，对于临床所用药物的配伍禁忌，有严格的使用规定，如：药物配伍禁忌表。2)对机体代谢处置能力的相互影响，是指一种药物影响机体负责药物代谢处置的组织和器官，对另外一种药物的体内过程产生重要影响，进而会引起药效以及毒性的改变。国内外药政部门颁布的药物相互作用影响的指导原则，针对的就是该部分。3)药物效应之间的相互影响，是指作用机制不同或者相似的药物合用时，药物效应的增强或者减弱。4)给药顺序(序贯)的影响，多个药物的合用会出现给药顺序的不同，所致组织细胞状态的改变不同，因而导致药物效应有所差别。
药政部门对前两者有明确的管理指导规范，而对后两者中有关药物合用时，药效协同、相加以及拮抗的定量检测，则缺乏具体的指导方法。不论药物相互作用发生于何种层面，药物的效应均会发生改变，出现协同、相加及拮抗。
而关于协同、相加及拮抗的定义，目前公认的定义是：协同是实际药效大于预期的相加作用，相加是实际药效等于预期的相加作用，拮抗是实际药效小于预期的相加作用。从药物效应层面上看，协同和拮抗，实际上是药物之间发生了相互作用；相加，则没有发生相互作用，故药物相加的定义又扩展为零相互作用。如果从药物剂量发生改变的角度来看，协同则是在相等药效水平下，药物合用剂量小于预期的合用剂量；相加则是在相等药效水平下，药物合用剂量等于预期的合用剂量；拮抗是在相等药效水平下，药物合用剂量大于预期的合用剂量。因此，多药合用所致的效应和用药剂量的改变，实际上是一个硬币的两面，均可用来定义多药合用引起的协同、相加和拮抗。
上述这些关于相加效应的说法，不论是基于药效还是基于剂量，某一确定组合的药物合用的预期相加效应均是一个确定的数值。通过将合用时的实际效应检测值与预期相加效应的数值进行比较，来定量计算和判断协同、相加和拮抗。然而，多药联合应用时，各药物成员及组合药的量效曲线情况复杂，以两种药物A和药物B联合应用为例，将各药物成员实际面临的状况和量效关系曲线的复杂情况，列举如下：
1)情况1：药物A有效应，药物B无效应，药物A和B联合应用，药物A的效应发生明显变化。此种情况下，两药联合应用预期的药物相加效应的量效曲线为单用药物A的量效曲线，较易对药物联合应用发生的协同效应或拮抗效应进行定量。
2)情况2：药物A和药物B均无效应，药物A和药物B联合应用，产生药物效应。此种情况下，两药联合应用预期的药物相加效应曲线为效应值为零的直线，较易对药物联合应用发生协同效应进行定量。
3)情况3：药物A有效应，药物B也有效应，药物A和B联合应用时，各自的药物效应则必然发生变化。既不同于单用药物A的效应，也不同于单用药物B的效应。各药物成员的量效曲线，既单独成立，又相互影响，确定预期相加效应曲线，则非常困难，面临的药物量效关系曲线有：
药物A单用时的量效关系曲线；
药物B单用时的量效关系曲线；
药物A和B，以某一固定比例联合时，药物A的量效曲线；
药物A和B，以某一固定比例联合时，药物B的量效曲线；
药物A，以某一固定剂量与药物B联合时，药物B的量效曲线；
药物B，以某一固定剂量与药物A联合时，药物A的量效曲线。
4)如果两药作用方式差别较大，必然会涉及给药序贯(次序)方式的不同所致量效关系的改变，大大增加了复杂性。
5)如果是三个以上药物联合应用，药物量效曲线变化的情况则更为复杂。
而关于多药联用时的药效为协同、相加或者拮抗的计算方法，在过去一百多年，已有许多文献发表了多种的计算方法，如：Greco WR在一篇综述中归纳、总结的关于协同和拮抗的计算方法，就有13种之多。而近二十年来，有关新方法的发展，进展较少。目前公认的经典方法，仍然是Loewe的等效线相加模型和Bliss的独立模型。
Loewe的等效线相加模型具体为：将两个药物A和B，在某一效应水平处的药物剂量DA和DB，分别标示于直角坐标系中X轴和Y轴上，连接两点的直线，则得到截距式直线方程为：
Figure PCTCN2016097514-appb-000001
Loewe指出，当两药分别在较小剂量dA和dB联合应用时，达到单用药物剂量DA或者DB产生的效应时，则存在以下关系：
Figure PCTCN2016097514-appb-000002
为相加效应；
Figure PCTCN2016097514-appb-000003
为协同效应；
Figure PCTCN2016097514-appb-000004
为拮抗效应。
等效线相加模型巧妙地避开了如何对预计相加作用进行计算的棘手问题。从相等药效情况下、合用剂量减少的角度，来评价药物协同、相加和拮抗。将相等效应下不同的剂量组合，描述成一条直线。通过不同合用组合剂量的坐标点与该直线的位置关系，判断协同、相加和拮抗。该计算方法被广泛使用，但适用范围有限，只能用于作用方式相似的两种药物，把“剂量比”等同于“效应比”，仅用于固定比例联合应用的评价，对更多药物合用的联合应用，评价则非常困难。
而Bliss独立模型具体为：药物A和药物B的效应是质反应资料，药物效应的量值范围为0～1。将两个药物的药物效应看成是独立的事件，借用概率相加计算公式PAB＝PA+PB–PA×PB，由此推理得出药物联合应用的相加效应为EAB＝EA+EB–EA×EB，则存在以下关系：
Figure PCTCN2016097514-appb-000005
为相加作用；
Figure PCTCN2016097514-appb-000006
为协同作用；
Figure PCTCN2016097514-appb-000007
为拮抗作用。
Bliss独立模型法，将概率相加公式引入，用于质反应药物的联合应用分析。但该方法缺乏药物A和药物B各自的量效关系的支持，仅把两药合用看作是两个孤立事件发生概率的相加。国内较多使用的金氏法，即来源于该模型，但该模型不符合药物量效关系的基本规律。
其余方法多是基于这两种方法的推导和演化(如：等效线图法、Bürgi公式法、分数分析法、中位效应法、效应表面模型、金氏公式法、分数乘积法等)，还有一些计算方法的数学公式则非常复杂，关键参数的设置往往依赖于使用者的经验，计算繁琐，很难精确计算多药合用药效变化的相关数据。
由此可见，当前对多药联合应用进行药效/毒效评价的方法，大多是停留在对药物合用组与药物单用组进行简单的定量比较。而对于两药合用效应的评价，仅能在一定条件之下，，用Loewe等效线相加模型及相关模型对两药固定比例的联合应用的药效进行计算；而对质反应效应数据，可选用Bliss独立模型进行计算。另外，还有一种更为简单的方法，即固定一个药的剂量，调整另外一个药的剂量，进行比较试验。而对于其他类型药物联合方式、更多药物 成员的联合应用以及新药多成分、复杂复方制剂的研发，则缺乏可靠的药效/毒效定量计算方法。
因此，基于上述复杂的状况，当多个药物联合应用时，如何定量评价多药联合应用所致效应的改变，如何确定其药物效应发生协同、相加和拮抗，并对其进行定量检测，长期以来一直没有得到解决。
发明内容
本发明的主要目的在于提供一种联用药的药效处理方法及处理装置，以解决现有技术中当多个药物联合应用时难以确定其药物效应的技术问题。
名词解释：
联用药：在本发明中，联用药是指用于联合应用的多种药，联用药根据联合应用的药物种类的多少而包含不同种类的药物。当两种药物联用时，联用药是指两种药；当三种药物联用时，联用药指的是三种药；当三种以上的多种药物联用时，联用药指的是三种以上的多种药。而本发明中的联用、合用、联合应用以及配伍都是指联用的意思。实施例中具体的不同药物按不同的联用条件形成的合用组也是联用药的意思。
量效关系：是指在一定剂量范围内，药物剂量的大小与药物效应成正比，这种关系称为剂量-效应关系，简称量效关系。
量效关系曲线：是指定量地反映药物效应随药物剂量或浓度变化的规律的曲线。
剂量合用指数：在横坐标轴上，沿某一确定的联用剂量点，作一垂直线，相交于量效曲带的分别为该联用剂量下预期相加效应的最小值和最大值。将联合用剂量的实际药效值分别与相加药效值范围的最大值和最小值进行比较，计算CId1和CId2。
效应合用指数：在纵坐标轴上，沿某一确定药效点，作一平行于横轴的直线，相交于量效曲带分别为该药效水平下产生预期相加效应所给予剂量的最小值和最大值。将产生实际该水平药效的联用剂量分别与相加剂量的最小值和最大值进行比较，计算CIe1和CIe2。
为了实现上述目的，根据本发明的一个方面，提供了一种联用药药效的处理方法，该处理方法包括：获取联用药的预期相加效应的量效曲带，量效曲带由多条等效量效曲线中最外围的两条围成，等效量效曲线是指以联用药中的某一目标组分药的剂量为横坐标，以联用药等效兑换为任意一组分药所获得的预期相加效应为纵坐标而建立的曲线；等效兑换按照所获取的联用药中各组分药的用药顺序进行等效兑换；获取联用药的实际效应值随联用药中的某一目标组分药的剂量变化形成的实际量效关系曲线；比较实际量效关系曲线与量效曲带的位置关系，以及当实际量效关系曲线位于量效曲带的上方时，将联用药的药效输出为协同；当实际量效关系曲线位于量效曲带的下方时，将联用药的药效输出为拮抗；当实际量效关系曲线位于量效曲带范围内时，将联用药的药效输出为相加。
进一步地，联用药包括第一组分药A和第二组分药B，在获取联用药的预期相加效应的量效曲带的步骤之前，处理方法还包括建立多条等效量效曲线的步骤；其中，建立多条等效量效曲线的步骤包括：获取第一组分药A的第一量效关系曲线Y＝f(x)；获取第二组分药B的第二量效关系曲线Y＝g(x)；查找或计算第一量效关系曲线Y＝f(x)上第一组分药A在联用剂量Am下的效应值f(Am)；查找或计算第二量效关系曲线Y＝g(x)上与效应值f(Am)相同的第二组份药B的效应值g(Bm)所对应的等效剂量值Bm；计算第二组分药B的联用剂量Bn与等效剂量Bm的剂量和(Bn+Bm)；查找或计算第二量效关系曲线Y＝g(x)上第二组分药B的剂量为剂量和(Bn+Bm)时所对应的效应值g(Bn+Bm)；将效应值g(Bn+Bm)转换为联用药的预期相加效应值Y(Am+Bn)；建立联用药的预期相加效应值随第一组分药A的剂量变化的第一等效量效曲线Y(Am+Bn)＝g(Bn+Bm)；查找或计算第二量效关系曲线Y＝g(x)上第二组分药B在联用剂量Bn下的效应值g(Bn)；查找或计算第一量效关系曲线Y＝f(x)上与效应值g(Bn)相同的第一组分药A的效应值f(An)所对应的等效剂量值An；计算第一组分药A的联用剂量Am与等效剂量An的剂量和(Am+An)；查找或计算第一量效关系曲线Y＝f(x)上第一组分药A的剂量为剂量和(Am+An)时所对应的效应值f(Am+An)；将效应值f(Am+An)转换为联用药的预期相加效应值Y(Am+Bn)；建立联用药的预期相加效应值随第一组分药A的剂量变化的第二等效量效曲线Y(Am+Bn)＝f(Am+An)。
进一步地，当联用药的药效输出结果为协同时，在将联用药的药效输出为协同的步骤后，处理方法还包括：计算实际量效关系曲线位于量效曲带的上方时所对应的某一目标组分药的第一剂量范围；以及将第一剂量范围输出为某一目标组分药的协同剂量范围。
进一步地，在输出某一目标组分药的协同剂量范围后，处理方法还包括：获取联用药中某一目标组分药与其余组分药之间的联用关系；根据联用关系计算联用药中其余组分药在联用条件下的协同剂量范围；以及输出其余组分药的协同剂量范围。
进一步地，当联用药的药效输出结果为拮抗时，在将联用药的药效输出为拮抗的步骤后，处理方法还包括：计算实际量效关系曲线位于量效曲带的下方时所对应的某一目标组分药的第二剂量范围，以及将第二剂量范围输出为某一目标组分药的拮抗剂量范围。
进一步地，在输出某一目标组分药的拮抗剂量范围后，处理方法还包括：获取联用药中某一目标组分药与其余组分药之间的联用关系；根据联用关系计算联用药中其余组分药在联用条件下的拮抗剂量范围；以及输出其余组分药的拮抗剂量范围。
进一步地，当联用药的药效输出结果为相加时，在将联用药的药效输出为相加的步骤后，处理方法还包括：计算实际量效关系曲线位于量效曲带范围内时所对应的某一目标组分药的第三剂量范围；以及将第三剂量范围输出为某一目标组分药的相加剂量范围。
进一步地，在输出某一目标组分药的相加剂量范围后，处理方法还包括：获取联用药中某一目标组分药与其余组分药之间的联用关系；根据联用关系计算联用药中其余组分药在联用条件下的相加剂量范围；以及输出其余组分药的相加剂量范围。
进一步地，比较实际量效关系曲线与量效曲带的位置关系的步骤包括：获取某一目标组分药在特定联用剂量下，对应的联用药在量效曲带范围内的预期相加效应的最小值和最大值；获取某一目标组分药在特定联用剂量下，对应的联用药在实际量效关系曲线上的实际效应值；计算实际效应值与预期相加效应的最小值的第一比值；计算实际效应值与预期相加效应的最大值的第二比值；将第一比值和第二比值分别标记为CId1和CId2；若CId1和CId2均大于1，则确定实际量效关系曲线位于量效曲带的上方；联用为协同。若CId1和CId2均小于1，则确定实际量效关系曲线位于量效曲带的下方；联用为拮抗。若CId1和CId2中任一个≧1或≦1，则确定实际量效关系曲线位于量效曲带的范围内。
进一步地，在将第一比值和第二比值分别标记为CId1和CId2的步骤后，处理方法还包括输出CId1和CId2的步骤。
进一步地，比较实际量效关系曲线与量效曲带的位置关系的步骤包括：获取联用药在量效曲带上产生特定效应时所对应的某一目标组分药的剂量的最小值和最大值；获取联用药在实际量效关系曲线上产生特定效应时所需要的实际联用剂量；计算实际联用剂量与最小值的第三比值；计算实际联用剂量与最大值的第四比值；将第三比值和第四比值分别标记为CIe1和CIe2；若CIe1和CIe2均小于1，则确定实际量效关系曲线位于量效曲带的上方；若CIe1和CIe2均大于1，则确定实际量效关系曲线位于量效曲带的下方；若CIe1和CIe2中任一个≧1或≦1，则确定实际量效关系曲线位于量效曲带的范围内。
进一步地，在将第三比值和第四比值分别标记为CIe1和CIe2的步骤后，处理方法还包括输出CIe1和CIe2的步骤。
根据本发明的另一方面，提供了一种联用药药效的处理装置，该处理装置包括：第一获取模块，用于获取联用药的预期相加效应的量效曲带，量效曲带由多条等效量效曲线中最外围的两条围成，每条等效量效曲线是指以联用药中的某一目标组分药的剂量为横坐标，以联用药等效兑换为任意一组分药所获得的预期相加效应为纵坐标而建立的曲线；等效兑换按照联用药中各组分药的用药顺序进行等效兑换；第二获取模块，用于获取联用药的实际效应值随联用药中的某一目标组分药的剂量变化形成的实际量效关系曲线；第一比较模块，用于比较实际量效关系曲线与量效曲带的位置关系，以及第一输出模块，用于当实际量效关系曲线位于量效曲带的上方时，将联用药的药效输出为协同；第二输出模块，用于当实际量效关系曲线位于量效曲带的下方时，将联用药的药效输出为拮抗；第三输出模块，用于当实际量效关系曲线位于量效曲带范围内时，将联用药的药效输出为相加。
进一步地，联用药包含第一组分药A和第二组分药B，处理装置还包括等效量效曲线建立模块，等效量效曲线建立模块用于在第一获取模块获取联用药的预期相加效应的量效曲带的步骤之前建立多条等效量效曲线；等效量效曲线建立模块包括：第一获取单元，用于获取第一组分药A的第一量效关系曲线Y＝f(x)；第二获取单元，用于获取第二组分药B的第二量效关系曲线Y＝g(x)；第一查找单元，用于查找或计算第一量效关系曲线Y＝f(x)上第一组分药A在联用剂量Am下的效应值f(Am)；第二查找单元，用于查找或计算第二量效关系曲线Y＝g(x)上与效应值f(Am)相同的第二组份药B的效应值g(Bm)所对应的等效剂量值Bm；第一计算单 元，用于计算第二组分药B的联用剂量Bn与等效剂量Bm的剂量和Bm+Bn；第三查找单元，用于查找或计算第二量效关系曲线Y＝g(x)上第二组分药B的剂量为计量和时所对应的效应值g(Bn+Bm)；第一转换单元，用于将效应值g(Bn+Bm)转换为联用药的预期相加效应值Y(Am+Bn)；以及第一曲线建立单元，用于建立联用药的预期相加效应随第一组分药A的剂量变化的第一等效量效曲线Y(Am+Bn)＝g(Bn+Bm)；第四查找单元，用于查找或计算第二量效关系曲线Y＝g(x)上第二组分药B在联用剂量Bn下的效应值g(Bn)；第五查找单元，用于查找或计算第一量效关系曲线Y＝f(x)上与效应值g(Bn)相同的第一组分药A的效应值f(An)所对应的等效剂量值An；第二计算单元，用于计算第一组分药A的联用剂量Am与等效剂量An的剂量和(Am+An)；第六查找单元，用于查找或计算第一量效关系曲线Y＝f(x)上第一组分药A的剂量为剂量和(Am+An)时所对应的效应值f(Am+An)；第二转换单元，用于将效应值f(Am+An)转换为联用药的预期相加效应值Y(Am+Bn)；第二曲线建立单元，用于建立联用药的预期相加效应值随第一组分药A的剂量变化的第二等效量效曲线Y(Am+Bn)＝f(Am+An)。
进一步地，处理装置还包括：第一计算模块，用于在第一输出模块将联用药的药效输出为协同后，计算实际量效关系曲线位于量效曲带的上方时所对应的某一目标组分药的第一剂量范围；以及第四输出模块，用于将第一剂量范围输出为某一目标组分药的协同剂量范围。
进一步地，处理装置还包括：第三获取模块，用于在第四输出模块将第一剂量范围输出为某一目标组分药的协同剂量范围之后，获取联用药中某一目标组分药与其余组分药之间的联用关系；第二计算模块，用于根据联用关系计算联用药中其余组分药在联用条件下的协同剂量范围；以及第五输出模块，用于输出其余组分药的协同剂量范围。
进一步地，处理装置还包括：第三计算模块，用于在第二输出模块后将联用药的药效输出为拮抗后，计算实际量效关系曲线位于量效曲带的下方时所对应的某一目标组分药的第二剂量范围，以及第六输出模块，用于将第二剂量范围输出为某一目标组分药的拮抗剂量范围。
进一步地，处理装置还包括：第四获取模块，用于在第六输出模块将第二剂量范围输出为某一目标组分药的拮抗剂量范围后，获取联用药中某一目标组分药与其余组分药之间的联用关系；第四计算模块，用于根据联用关系计算联用药中其余组分药在联用条件下的拮抗剂量范围；以及第七输出模块，用于输出其余组分药的拮抗剂量范围。
进一步地，处理装置还包括：第五计算模块，用于在第三输出模块将联用药的药效输出为相加后，计算实际量效关系曲线位于量效曲带范围内时所对应的某一目标组分药的第三剂量范围；以及第八输出模块，用于将第三剂量范围输出为某一目标组分药的相加剂量范围。
进一步地，处理装置还包括：第五获取模块，用于在第八输出模块将第三剂量范围输出为某一目标组分药的相加剂量范围后，获取联用药中某一目标组分药与其余组分药之间的联用关系；第六计算模块，用于根据联用关系计算联用药中其余组分药在联用条件下的相加剂量范围；以及第九输出模块，用于输出其余组分药的相加剂量范围。
进一步地，第一比较模块包括：第一获取子模块，用于获取某一目标组分药在特定联用剂量下，对应的联用药在量效曲带范围内的预期相加效应的最小值和最大值；第二获取子模 块，用于获取某一目标组分药在特定联用剂量下，对应的联用药在实际量效关系曲线上的实际效应值；第一计算子模块，用于计算实际效应值与预期相加效应的最小值的第一比值；第二计算子模块，用于计算实际效应值与预期相加效应的最大值的第二比值；第一标记子模块，用于将第一比值和第二比值分别标记为CId1和CId2；第一确定子模块，用于当CId1和CId2均大于1时，确定实际量效关系曲线位于量效曲带的上方；第二确定子模块，用于当CId1和CId2均小于1，确定实际量效关系曲线位于量效曲带的下方；以及第三确定子模块，用于当CId1和CId2中任一个≧1或≦1，确定实际量效关系曲线位于量效曲带的范围内。
进一步地，处理装置还包括第十一输出模块，用于在第一标记子模块将第一比值和第二比值分别标记为CId1和CId2之后，输出CId1和CId2。
进一步地，第一比较模块包括：第三获取子模块，用于获取联用药在量效曲带上产生特定效应时所对应的某一目标组分药的剂量的最小值和最大值；第四获取子模块，用于获取联用药在实际量效关系曲线上产生特定效应时所需要的实际联用剂量；第三计算子模块，用于计算实际联用剂量与最小值的第三比值；第四计算子模块，用于计算实际联用剂量与最大值的第四比值；第二标记子模块，用于将第三比值和第四比值分别标记为CIe1和CIe2；第四确定子模块，用于当CIe1和CIe2均小于1时，确定实际量效关系曲线位于量效曲带的上方；第五确定子模块，用于当CId1和CId2均大于1时，确定实际量效关系曲线位于量效曲带的下方；以及第六确定子模块，用于当CId1和CId2中任一个≧1或≦1时，确定实际量效关系曲线位于量效曲带的范围内。
进一步地，处理装置还包括第十二输出模块，用于在第二标记子模块将第三比值和第四比值分别标记为CIe1和CIe2后，输出CId1和CId2。
为了实现上述目的，根据本发明的一个方面，提供了一种存储介质。上述存储介质用于保存上述任一种联用药药效处理方法所执行的程序代码。
根据本发明的又一个方面，提供一种计算机终端，该计算机终端包括：一个或多个处理器、存储器以及传输装置，其中，存储器用于存储联用药药效处理方法和/或装置对应的程序指令和/或模块，处理器通过运行存储在存储器内的程序指令和/或模块，从而执行各种功能应用以及数据处理，实现上述的联用药药效处理方法。
应用本发明的技术方案，通过基于联用药的预期相加效应的量效曲带，与联用药的实际量效曲线进行比对，然后通过实际量效曲线与量效曲带的位置关系来判断联用药的药效。由于量效曲带更符合药物的量效关系以及药物联用时的药效学基本特征，该实施例的药效处理方法综合了多种药物在联用时的用药次序的不同以及不同药物量效关系的不同对联用药药效的影响，不仅能够实现对多种(两种及两种以上)药物联用时的药效进行检测，而且能够实现定量检测。上述处理方法不仅解决了现有技术中多药联用时的药效无法准确检测的问题，而且所检测得到的联用药的药效能够广泛应用于复方药的研发、毒理学研究以及环境评价中。此外，根据需要还能够定量计算多个药物在不同的联用条件下，产生协同、相加和拮抗的剂量范围以及其他药物联用的相关指标。
附图说明
构成本申请的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。在附图中：
图1示出了本申请的一种优选实施例中联用药的药效处理方法的流程示意图；
图2示出了本申请的一种优选实施例中联用药的药效处理装置的结构示意图；
图3A至图3D示出了根据本申请的实施例1的硝羟基化合物(NX)和紫杉醇(TX)单用及合用组中的药物NX的量效关系曲线；其中，图3A至图3B分别示出了硝羟基化合物(NX)和紫杉醇(TX)两种单药的量效关系曲线；图3C示出了当NX+TX以固定比例合用时，合用组的实际药效随其中药物NX的剂量变化的量效关系曲线；图3D示出了当NX不同剂量+TX固定剂量合用时，合用组的实际药效随其中药物NX的剂量变化的量效关系曲线；
图4示出了本申请的实施例1中当NX+TX按固定比例合用时，以合用组的NX各剂量水平为横坐标，以各预期相加效应值为纵坐标作图，构成预期相加效应的量效曲带图以及实际量效关系曲线；
图5示出了上述图4中当NX+TX按固定比例合用时，通过增加多个NX+TX联用的具体联用剂量点，然后以合用组的NX各剂量水平为横坐标，以各预期相加效应值和实际效应值为纵坐标作图，构成预期相加效应的量效曲带以及实际量效关系曲线；
图6示出了上述图5中在ED50药效水平线与预期相加效应的相交剂量点为A和B，与实际效应的相交剂量点为C，实际效应的相交剂量点大于预期相加效应的剂量范围点，位于量效曲带的下方；
图7示出了本申请实施例1中当TX固定浓度+NX不同比例合用时，以合用组的NX各剂量水平为横坐标，以各预期相加效应值为纵坐标作图，构成预期相加效应的量效曲带图以及实际量效关系曲线；
图8A至图8D示出了根据本申请的实施例2的三药依托泊苷(A)、长春新碱(B)和5-氟尿嘧啶(C)，单药和药物合用组中的依托泊苷(A)的量效曲线；其中，图8A至8C分别示出了三种单药依托泊苷(A)、长春新碱(B)和5-氟尿嘧啶(C)的量效关系曲线；图8D示出了药物合用组中的依托泊苷(A)的量效关系曲线；
图9A以合用组的依托泊苷(A)各剂量水平为横坐标，以三个(A+B)+C、(A+C)+B、(B+C)+A组合的预期相加效应值和实际效应值的数据为纵坐标，作出的12条量效曲线以及实际量效曲线；
图9B示出了以合用组的依托泊苷(A)各剂量水平为横坐标，以三个(A+B)+C、(A+C)+B、(B+C)+A组合的预期相加效应值和实际效应值的数据为纵坐标，作出的12条量效曲线中最外围的两条曲线所围成的量效曲带以及实际量效曲线；
图10示出了本发明的实施例2中A、B、D三药合用组固定比例A:B:D＝12.5:2:4(μg/ml)预期相加效应和实际效应的比较图；
图11示出了本发明的实施例2中A、C、D三药合用组固定比例A:C:D＝12.5:45:4(μg/ml)预期相加效应和实际效应的比较图；以及
图12示出了本发明的实施例2中B、C、D三药合用组按固定比例B:C:D＝2:45:4(μg/ml)联用的预期相加效应和实际效应的比较图。
具体实施方式
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将结合实施例来详细说明本发明。
为了使本技术领域的人员更好地理解本申请的方案，下面将结合本申请实施例中的附图，对本申请实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本申请一部分的实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都应当属于本申请保护的范围。
需要说明的是，本申请的说明书和权利要求书及上述附图中的术语“第一”、“第二”等是用于区别类似的对象，而不必用于描述特定的顺序或先后次序。应该理解这样使用的数据在适当情况下可以互换，以便这里描述的本申请的实施例能够以除了在这里图示或描述的那些以外的顺序实施。此外，术语“包括”和“具有”以及他们的任何变形，意图在于覆盖不排他的包含，例如，包含了一系列步骤或单元的过程、方法、系统、产品或设备不必限于清楚地列出的那些步骤或单元，而是可包括没有清楚地列出的或对于这些过程、方法、产品或设备固有的其它步骤或单元。
在附图的流程图示出的步骤可以在诸如一组计算机可执行指令的计算机系统或者软件中执行，并且，虽然在流程图中示出了逻辑顺序，但是在某些情况下，可以以不同于此处的顺序执行所示出或描述的步骤。
本申请实施例所提供的方法可以在移动终端、计算机终端或者类似的运算装置中执行。
可选地，在本实施例中，上述多药联用时的药效检测方法可以应用于网络环境。在本实施例中，上述多药联用时的药效检测方法可以应用于终端和服务器所构成的硬件网络环境中。终端通过网络与服务器进行连接，上述网络包括但不限于：广域网、城域网或局域网。在本发明实施例中，上述的终端可以为移动终端、个人电脑上，具体地，终端可以为智能手机、平板电脑、PDA等终端。
在上述运行环境下，本申请提供了如图1所示的一种联用药药效的处理方法。图1是根据本申请实施例的联用药药效的处理方法的流程图。
如图1所示，该处理方法包括如下步骤：
步骤S202：获取联用药的预期相加效应的量效曲带，量效曲带由多条等效量效曲线最外围的两条围成，每条等效量效曲线是指以联用药中的某一目标组分药的剂量为横坐标，以联用药等效兑换为任意一组分药所获得的预期相加效应为纵坐标而建立的曲线；等效兑换按照所获取的联用药中各组分药的用药顺序进行等效兑换；
步骤S204：获取联用药的实际效应值随联用药中的某一目标组分药的剂量变化形成的实际量效关系曲线；
步骤S206：比较实际量效关系曲线与量效曲带的位置关系，以及
步骤S208：当实际量效关系曲线位于量效曲带的上方时，将联用药的药效输出为协同；当实际量效关系曲线位于量效曲带的下方时，将联用药的药效输出为拮抗；当实际量效关系曲线位于量效曲带范围内时，将联用药的药效输出为相加。
其中，所获取的联用药中各组分药的用药顺序中包括各组分药的联用剂量或浓度，以及各组分药的量效关系曲线。
本申请的上述处理方法通过基于联用药的预期相加效应的量效曲带，与联用药的实际量效曲线进行比对，然后通过实际量效曲线与量效曲带的位置关系来判断联用药的药效。由于量效曲带更符合药物的量效关系以及药物联用时的药效学基本特征，该实施例的药效处理方法综合了多种药物在联用时的用药次序的不同以及不同药物量效关系的不同对联用药药效的影响，不仅能够实现对多种(两种及两种以上)药物联用时的药效进行检测，而且能够实现定量检测。上述处理方法不仅解决了现有技术中多药联用时的药效无法准确检测的问题，而且所检测得到的联用药的药效能够广泛应用于复方药的研发、毒理学研究以及环境评价中。此外，根据需要还能够定量计算多个药物在不同的联用条件下，产生协同、相加和拮抗的剂量范围以及其他药物联用的相关指标(比如合用指数CId及CIe)。
具体地，在获取联用药中各组分药的量效关系曲线后，根据等效兑换原则，将联用药的预期相加效应等效兑换为各组分药的预期相加效应，然后建立各条联用药的预期相加效应随某一目标组分药的剂量变化形成的等效量效曲线，然后获取多条等效量效曲线中最外围的两条所围成的曲带从而得到联用药的预期相加效应的量效曲带；同时或在获取上述量效曲带之后，获取联用药的实际效应值随联用药中的某一目标组分药的剂量变化形成的实际量效关系曲线；然后比较量效曲带和实际量效曲线之间的位置关系，根据实际量效曲线位于量效曲带的上方、下方或范围内，相应地，输出联用药的药效为协同、拮抗或相加。
上述实施例中，根据联用药的种类的多少及组分药顺序组合的不同，通过将联用药的预期相加效应分别等效兑换为每一组分药的等效量效曲线，使得到的联用药的预期相加效应的量效曲线都与每一组分药自身的量效曲线相同，由于相加效应是零相互作用，当多种药物同时暴露于机体组织中的每一个药效执行单元时，药效发挥作用的先后顺序是随机的。因而，联用药的预期相加效应，是所有药效执行单元的效应的总和。一个药效执行单元表现的药效发挥顺序为在第一组分药A发挥效应的基础上B再沿B自身的量效曲线发挥自身剂量的效应； 而另一个药效执行单元则可能表现为在第二组分药B发挥效应的基础上，A再沿A自身的量效曲线发挥自身剂量的效应。用公式表示即为：
Figure PCTCN2016097514-appb-000008
其中，Lo＝Low，Hi＝High；
Figure PCTCN2016097514-appb-000009
表示数集内单元的函数值，须按照从低(Low)到高(High)排列；Bn和An是等效剂量，Am和Bm是等效剂量。
因此，两药在某一确定剂量联用时(Am和Bn)，预期相加效应值是一个范围，即为一个数集，两个预期相加效应值为该数集的边界值，分别代表所有的药效执行单元为百分之百的Am→Bn和百分之百的Bn→Am，中间的数值范围为不同比例的Am→Bn和Bn→Am药效执行单元药效的累积之和。预期相加效应值在该数集范围内更符合量效曲带关系，而不是现有技术中的一条直线。
可选地，上述联用药中包括第一组分药A和第二组分药B，在获取上述联用药的预期相加效应的量效曲带的步骤之前，该处理方法还包括建立多条等效量效曲线的步骤，其中，建立多条等效量效曲线的步骤包括：获取第一组分药A的第一量效关系曲线Y＝f(x)，获取第二组分药B的第二量效关系曲线Y＝g(x)，查找或计算第一量效关系曲线Y＝f(x)上第一组分药A在联用剂量Am下的效应值f(Am)，查找或计算第二量效关系曲线Y＝g(x)上与效应值f(Am)相同的第二组份药B的效应值g(Bm)所对应的等效剂量值Bm，计算第二组分药B的联用剂量Bn与等效剂量Bm的剂量和Bm+Bn，查找或计算得到第二量效关系曲线Y＝g(x)上第二组分药B的剂量为计量和Bm+Bn时所对应的效应值g(Bn+Bm)，将效应值g(Bn+Bm)转换为联用药的预期相加效应值Y(Am+Bn)，建立联用药的预期相加效应随第一组分药A的剂量变化的第一等效量效曲线Y(Am+Bn)＝g(Bn+Bm)；查找或计算第一量效关系曲线Y＝f(x)上与效应值g(Bn)相同的第一组分药A的效应值f(An)所对应的等效剂量值An，计算第一组分药A的联用剂量Am与等效剂量An的剂量和(Am+An)，查找或计算第一量效关系曲线Y＝f(x)上第一组分药A的剂量为剂量和(Am+An)时所对应的效应值f(Am+An)，将效应值f(Am+An)转换为联用药的预期相加效应值Y(Am+Bn)，建立联用药的预期相加效应值随第一组分药A的剂量变化的第二等效量效曲线Y(Am+Bn)＝f(Am+An)。
上述建立等效量效曲线的过程是将第一组分药A的联用剂量下产生的效应等效兑换为第二组分药B，即将联用药的预期相加效应等效兑换为第二组分药B的剂量和所对应的效应值；同理，当将第二组分药B的联用剂量下产生的效应等效兑换为第一组分药A时，重复上述步骤，则建立的等效量效曲线是将第二组分药B的联用剂量下产生的效应等效兑换为第一组分药A，将联用药的预期相加效应等效兑换为第一组分药A的剂量和所对应的效应值。由于两种药物联用时的用药顺序也有先用A再用B，或者先用B再用A，因而，联用药的预期相加效应的等效量效曲线有上述两条。那么，上述两条等效量效曲线所围成的量效曲带就是两药联用时的预期相加效应的量效曲带。
与上述两种药联用的预期相加效应的等效量效曲线的建立步骤相同，三种药联用的预期相加效应是在任意两药相加效应基础上，第三个药物沿着自己的量效曲线达到自身剂量的药 效水平，即该联用药的预期相加效应与第三个药物的量效曲线进行等效剂量兑换后，该等效剂量与第三个药物剂量合并，遵循第三个药物的量效关系函数得出的函数值，即为三药联用的预期相加效应值。反过来也成立，在一个药物效应基础上，另外任意相加的两药沿着自身相加效应的量效曲线达到自身剂量的药效水平。而其中任意两药的相加效应即为上述当联用药含有第一组分药A和第二组分药B两种药时所得到的预期相加效应曲带。也就是说，三种药联用的预期相加效应是在任意两药根据其联用剂量转换为其中一种组分药时的等效量效曲线的基础上，第三个药物沿着自己的量效曲线达到自身剂量的药效水平。反之亦然。
药物a、药物b和药物c有三种不同的用药顺序组合，分别为(a+b)+c、(a+c)+b、(b+c)+a，每一种用药顺序组合中按照上述第一组分药A和第二组分药B的等效兑换原则，将第一组分药更新为药物(a+b)、(a+c)和(b+c)，则(a+b)+c的顺序组合的预期相加效应可以将(a+b)等效兑换为c的等效量效曲线，也可以等效兑换为(a+b)的等效量效曲线，而(a+b)的等效量效曲线又可以等效兑换为a的等效量效曲线，也可以兑换为b的等效量效曲线，因而(a+b)+c的联用药的预期相加效应具有4条等效量效曲线；根据上述用药组合的不同，重复上述等效量效曲线建立的过程，则得到12条等效量效曲线，其中最外围的两条所围成的曲带即为三药联用的预期相加效应的量效曲带。
与上述两种药联用和三种药联用的预期相加效应的等效量效曲线的建立步骤相同，四种药联用的预期相加效应的计算是两种情况之和。1)是在任意三药相加效应基础上，第四种组分药沿着自己的量效曲线达到自身剂量的药效水平，即该联用药的预期相加效应与第四种组分药的量效曲线进行等效剂量兑换后，该等效剂量与第四种组分药的剂量合并，遵循第四种组分药的量效关系函数得出的函数值，即为四药联用的预期相加效应值。反过来也成立，在其中一种组分药的效应基础上，另外任意相加的三药沿着自身相加效应的量效曲带达到自身剂量的药效水平。2)是在任意两药相加效应基础上，另外一组两药合用组合沿着自身的量效曲带达到自身的药效水平，等效兑换原则同上。
当5种、6种、…n种药物联用时，只需根据联用药种类不同和所形成的药物组合的多少和药物组合顺序的不同，重复执行上述建立等效量效曲线的步骤，逐步迭代循环即可建立所有等效量效曲线，然后获取所有等效量效曲线中最外围的曲线所围成的曲带即可得到多药联用的预期相加效应的量效曲带。
由上可知，无论联用药是2种、3种、4种，还是n种药，其在建立等效量效曲线的步骤中都包含了两种药之间相互等效兑换建立等效量效曲线的步骤，因而上述实施例中所述描述的等效量效曲线建立的步骤涵盖了所有≥2的联用药在建立等效量效曲线中所共有的步骤，因而，在获取n(n≥2)种联用药预期相加效应的量效曲带时，任何利用包含上述建立等效量效曲线的步骤都在本申请的范围内。
可选地，当联用药的药效输出结果为协同时，在将联用药的药效输出为协同的步骤后，上述处理方法还包括：计算实际量效关系曲线位于量效曲带的上方时所对应的某一目标组分药的第一剂量范围；以及将第一剂量范围输出为某一目标组分药的协同剂量范围。
具体地，根据实际量效关系曲线与量效曲带的函数关系，能够计算得出某一目标组分药在实际量效关系曲线与量效曲带交点处的剂量，根据该剂量即可计算得到位于交点上方的属于协同效应所对应的第一剂量范围。
可选地，在输出某一目标组分药的协同剂量范围后，上述处理方法还包括：获取联用药中某一目标组分药与其余组分药之间的联用关系；根据联用关系计算联用药中其余组分药在联用条件下的协同剂量范围；以及输出其余组分药的协同剂量范围。
具体地，获取联用药中某一目标组分药与其余组分药之间的联用关系，可以根据在先获取的联用药中各组分要的联用关系获得。比如，当联用药为A、B和C三种时，三种药以A：B：C＝2：2：5(μg/ml+μg/ml+μg/ml)的固定比例进行联用，当A为目标组分药物时，根据三种药物联用的预期相加效应曲带与实际量效关系曲线相交位置的剂量，可以计算得到当联用药的药效为协同时，A组分药的协同剂量范围；根据A组分药与B组分药为1：1的配比关系，可以得出B组分药的协同剂量范围；同理，根据A组分药与C组分药为2：5的配比关系，也可以得到C组分药的协同剂量范围。
同样，当联用药是以其他联用条件进行联用时，也可以根据具体联用条件的不同，得到其余组分药的协同剂量范围。比如，当A和B两种药联用，其中A以固定的1ng//ml的浓度与不同浓度(μg/ml)的B药μg/ml进行联用时，当计算得到目标药物B的协同剂量范围时，A组分药的协同剂量范围即为联用的固定剂量。
在得到各组分的协同剂量范围的基础上，将得到各组分的协同剂量范围进行相加，即可得到联用药的药效为协同的协同剂量范围。在实际应用中，也可以根据复方药的研发、毒理学研究以及环境评价的需要，得到上述目标药物的协同剂量范围以及相关剂量合用指数和/或效应合用指数。
可选地，当联用药的药效输出结果为拮抗时，在将联用药的药效输出为拮抗的步骤后，上述处理方法还包括：计算实际量效关系曲线位于量效曲带的下方时所对应的某一目标组分药的第二剂量范围，以及将第二剂量范围输出为某一目标组分药的拮抗剂量范围。
具体地，计算实际量效关系曲线位于量效曲带的下方时所对应的某一目标组分药的第二剂量范围的计算方法，也可以根据实际量效关系曲线位于量效曲带相交位置处所对应的剂量，然后得出效应位于该剂量效应下方的剂量的范围，即为某一目标组分药的拮抗剂量范围。在实际应用中，还可以根据复方药的研发、毒理学研究以及环境评价的需要，得到目标药物的拮抗剂量范围。
可选地，在输出某一目标组分药的拮抗剂量范围后，该处理方法还包括：获取联用药中某一目标组分药与其余组分药之间的联用关系；根据联用关系计算联用药中其余组分药在联用条件下的拮抗剂量范围；以及输出其余组分药的拮抗剂量范围。
其余组分的拮抗剂量范围与协同剂量范围的计算方法相同，都是根据联用药中各组分药之间的联用关系，在得到某一目标组分药的拮抗剂量范围后，按照上述协同剂量范围相同的算法得到其余组分药的拮抗剂量范围。
可选地，当联用药的药效输出结果为相加时，在将联用药的药效输出为相加的步骤后，处理方法还包括：计算实际量效关系曲线位于量效曲带范围内时所对应的某一目标组分药的第三剂量范围；以及将第三剂量范围输出为某一目标组分药的相加剂量范围。
某一目标组分药的相加剂量范围与其协同剂量范围的计算范围相同，实际量效曲线与量效曲带的交点处即为联用药处于相加效应时该某以目标组分药的最小剂量和最大剂量，两剂量之间的剂量即为相加效应的剂量范围。
可选地，在输出某一目标组分药的相加剂量范围后，处理方法还包括：获取联用药中某一目标组分药与其余组分药之间的联用关系；根据联用关系计算联用药中其余组分药在联用条件下的相加剂量范围；以及输出其余组分药的相加剂量范围。
其余组分药的相加剂量范围与协同剂量范围的计算方法相同，都是根据联用药中各组分药之间的联用关系，在得到上述某一目标组分药的相加剂量范围后，按照上述协同剂量范围相同的算法得到其余组分药的相加剂量范围。
可选地，当联用药包括第一组分药A和第二组分药B时，上述计算某一目标组分药的相加剂量范围除了上述提到的根据实际量效关系曲线与量效曲带交点处的剂量来计算外，还可以通过执行如下步骤实现：
以上述剂量和(Bn+Bm)的变化数值为横坐标，分别以联用药实际效应值和预期相加效应值为纵坐标建立第一合并剂量实际效应曲线Y’(Am+Bn)＝g(Bn+Bm)和第一合并剂量预期相加效应曲线Y”(Am+Bn)＝p(Bn+Bm)；
计算上述第一合并剂量实际效应曲线Y’(Am+Bn)＝g(Bn+Bm)和第一合并剂量预期相加效应曲线Y”(Am+Bn)＝p(Bn+Bm)的交点所对应效应值Y(Am+Bn)1；
获取联用药实际效应值随第一组分药A剂量变化的实际量效关系曲线Y(Am+Bn)＝h(m)；
计算上述效应值Y(Am+Bn)1在上述实际量效关系曲线Y(Am+Bn)＝h(m)上所对应的第一组分药A的联用剂量Am1；
以上述剂量和(An+Am)的变化数值为横坐标，分别以联用药实际效应值和预期相加效应值为纵坐标建立第二合并剂量实际效应曲线Y’(Am+Bn)＝f(Am+An)和第二合并剂量预期相加效应曲线Y”(Am+Bn)＝q(Bn+Bm)；
计算上述第二合并剂量实际效应曲线Y’(Am+Bn)＝f(Am+An)和第二合并剂量预期相加效应曲线Y”(Am+Bn)＝q(Bn+Bm)的交点所对应的效应值Y(Am+Bn)2；
计算上述效应值Y(Am+Bn)2在上述实际量效关系曲线Y(Am+Bn)＝h(m)上所对应的第一组分药A的联用剂量Am2；
将上述联用剂量Am1与联用剂量Am2之间的剂量作为联用药药效为相加效应时的第一组分药A的剂量范围；
根据第一组分药A与第二组分药B之间的联用关系，计算第二组分药B在联用药药效为相加效应时的剂量范围。
上述相加效应时的各组分间的剂量范围的计算方法同样适用于三种以三种以上的组分药联用，当联用药的种类≧2种时，按照上述步骤可以得到多个类似于第一组分药A的联用剂量Am1和Am2的相加效应剂量值形成的集合，选取该集合中的最小值和最大值作为≧2种的联用药相加效应的剂量范围。同样，其余组分的相加效应剂量范围根据联用条件即可计算得到。该方法在计算相加效应剂量范围时更方便。
可选地，比较实际量效关系曲线与量效曲带的位置关系的步骤包括：获取某一目标组分药在特定联用剂量下，对应的联用药在量效曲带范围内的预期相加效应的最小值和最大值；获取某一目标组分药在特定联用剂量下，对应的联用药在实际量效关系曲线上的实际效应值；计算实际效应值与预期相加效应的最小值的第一比值；计算实际效应值与预期相加效应的最大值的第二比值；将第一比值和第二比值分别标记为CId1和CId2；若CId1和CId2均大于1，则确定实际量效关系曲线位于量效曲带的上方；若CId1和CId2均小于1，则确定实际量效关系曲线位于量效曲带的下方；若CId1和CId2中任一个大于等于1或小于等于1，则确定实际量效关系曲线位于量效曲带的范围内。
上述实施例便于在任一给定的剂量下，判断不同效应值水平上实际量效关系曲线与量效曲带之间的位置关系。当给予相同的剂量时，实际量效关系曲线上对应的效应值分别与量效曲带上对应的预期相加效应的最小值和最大值相比，得到基于剂量的合用指数CId1和CId2；并根据CId1和CId2同时大于1，可判断实际量效关系曲线是在量效曲带的上方；CId1和CId2同时小于1，可判断实际量效关系曲线是在量效曲带的上方；而CId1和CId2其中之一大于等于1，或者CId1和CId2其中之一小于等于1，即表明其中一个实际效应值是在预期相加效应的量效曲带上，是相加效应。
可选地，在将上述第一比值和上述第二比值分别标记为CId1和CId2的步骤后，上述处理方法还包括输出CId1和CId2的步骤。该步骤利于在实际复方药的研发、毒理学研究以及环境评价的应用中，根据实际的药物联用情况，得到剂量合用指数。
可选地，比较实际量效关系曲线与量效曲带的位置关系的步骤，还可以是包括：获取联用药在量效曲带上产生特定效应时所对应的某一目标组分药的剂量的最小值和最大值；获取联用药在实际量效关系曲线上产生特定效应时所需要的实际联用剂量；计算实际联用剂量与最小值的第三比值；计算实际联用剂量与最大值的第四比值；将第三比值和第四比值分别标记为CIe1和CIe2；若CIe1和CIe2均小于1，则确定实际量效关系曲线位于量效曲带的上方；若CIe1和CIe2均大于1，则确定实际量效关系曲线位于量效曲带的下方；若CIe1和CIe2中任一个大于等于1或小于等于1，则确定实际量效关系曲线位于量效曲带的范围内。
上述实施例便于在任一给定药效水平下，比较不同剂量范围内实际量效曲线与量效曲带之间的位置关系。当在某一特定的药效值时，比如ED50，在联用药的量效关系曲带上纵坐标为50处作一条平行于横坐标的直线，分别于量效曲带和实际量效曲线相较于A、B和C三点，从而得到A、B和C三点所对应的横坐标数值，假如分别为1.012、1.321和1.450。则在药效ED50处，某一目标组分药的预期相加效应的剂量最小值为1.012，最大值为1.321，而实际效应的剂量为1.450，由于CIe1＝1.450/1.012>1，CIe2＝1.450/1.321>1；表明在产生相同的药效时，实际所需要给予的某一目标组分药的剂量大于预期所需要的剂量，因而在该效应值下，实际量效关系曲线位于量效曲带的下方，药效为拮抗。同理，若CIe1和CIe2小于1，则确定实际量效关系曲线位于量效曲带的上方；若CIe1和CIe2大于1，则确定实际量效关系曲线位于量效曲带的下方；若CIe1或CIe2大于等于1，则确定实际量效关系曲线位于量效曲带的范围内。
上述实施例的位置关系比较方法由于基于量效曲带，在相同剂量条件下或者在某一给定药效水平下，基于与预期相加效应在量效曲带上的两个效应值或两个剂量值，从而能够根据联用药的合用指数更准确地定量检测联用药的药效。比如，当CIe1<1且CIe2<1时，确定实际量效关系曲线位于量效曲带的下方，联用药的药效属于协同。若CIe1和CIe2的具体数值与1相距越远，表明联用药的协同效应越强；若CIe1和CIe2的具体数值与1相距越近，表明联用药的协同效应越弱，因而能够相对定量地检测联用药的药效水平。
可选地，在将上述第三比值和上述第四比值分别标记为CIe1和CIe2的步骤后，上述处理方法还包括输出CIe1和CIe2的步骤。根据实际应用中，复方药的研发、毒理学研究以及环境评价的需要，能够得到效应合用指数。
需要说明的是，对于前述的各方法实施例，为了简单描述，故将其都表述为一系列的动作组合，但是本领域技术人员应该知悉，本申请并不受所描述的动作顺序的限制，因为依据本申请，某些步骤可以采用其他顺序或者同时进行。其次，本领域技术人员也应该知悉，说明书中所描述的实施例均属于优选实施例，所涉及的动作并不一定是本申请所必须的。
通过以上的实施方式的描述，本领域的技术人员可以清楚地了解到根据上述实施例的联用药药效的处理方法可借助软件加必需的通用硬件平台的方式来实现，当然也可以通过硬件，但很多情况下前者是更佳的实施方式。基于这样的理解，本申请的技术方案本质上或者说对现有技术做出贡献的部分可以以软件产品的形式体现出来，该计算机软件产品存储在一个存储介质(如ROM/RAM、磁碟、光盘)中，包括若干指令用以使得一台终端设备(可以是手机，计算机，服务器，或者网络设备等)执行本申请各个实施例所述的方法。
根据本申请的实施例，还提供了一种联用药药效的处理装置，如图2所示，该处理装置包括：第一获取模块10、第二获取模块30、第一比较模块50、第一输出模块71、第二输出模块73和第三输出模块75；
其中，第一获取模块10，用于获取联用药的预期相加效应的量效曲带，量效曲带由多条等效量效曲线中最外围的两条围成，每条等效量效曲线是指以联用药中的某一目标组分药的 剂量为横坐标，以联用药等效兑换为每一组分药所获得的预期相加效应为纵坐标而建立的曲线；等效兑换按照联用药中各组分药的用药顺序进行等效兑换；
第二获取模块30，用于获取联用药的实际效应值随联用药中的某一目标组分药的剂量变化形成的实际量效关系曲线；
第一比较模块50，用于比较实际量效关系曲线与量效曲带的位置关系，以及
第一输出模块71，用于当实际量效关系曲线位于量效曲带的上方时，将联用药的药效输出为协同；
第二输出模块73，用于当实际量效关系曲线位于量效曲带的下方时，将联用药的药效输出为拮抗；
第三输出模块75，用于当实际量效关系曲线位于量效曲带范围内时，将联用药的药效输出为相加。
本申请的上述实施例方案中，在通过第一获取模块和第二获取模块在分别获取联用药的预期相加效应的量效曲带和实际量效关系曲线后，利用第一比较模块对实际量效关系曲线与量效曲带的位置关系进行比较，得到比较结果，最后根据比较结果的不同，选择经过第一输出模块、第二输出模块或者第三输出模块分别输出联用药的不同药效。
在上述实施例方案中，由于联用药量效曲带不仅能够用数学函数表示联用药的预期相加效应，而且该量效曲带是符合药物的量效关系及多药联用时的药效学特征的。此外，量效曲带还综合了药效的发挥作用顺序对联用药药效的影响及药效执行单元执行联用药中各组分药的先后顺序对最终联用药的药效的影响。因而，通过利用联用药的量效曲带与实际量效关系曲线之间的位置关系进行比较，不仅能够准确得出的联用药的药效，而且能够得到与联用药相关的各种指标。
具体地，在第一获取模块获取联用药中各组分药的量效关系曲线后，根据等效兑换原则，将联用药的预期相加效应等效兑换为各组分药的预期相加效应，然后建立各条联用药的预期相加效应随某一目标组分药的剂量变化形成的等效量效曲线，然后获取多条等效量效曲线中最外围的两条所围成的曲带从而得到联用药的预期相加效应的量效曲带；同时，在第二获取模块获取联用药的实际效应值随联用药中的某一目标组分药的剂量变化形成的实际量效关系曲线后；执行第一比较模块对量效曲带和实际量效曲线之间的位置关系进行比较，最后根据比较结果为实际量效曲线位于量效曲带的上方、下方或范围内，相应地，利用第一输出模块、第二输出模块或者第三输出模块分别将联用药的药效输出为协同、拮抗或相加。
上述实施例中，根据联用药的种类多少及组分药顺序组合的不同，通过将联用药的预期相加效应分别等效兑换为各组分药的等效量效曲线，使得到的联用药的预期相加效应的量效曲线都与每一组分药自身的量效曲线相同，由于相加效应是零相互作用，当多种药物同时暴露于机体组织中的每一个药效执行单元时，药效发挥作用的先后顺序是随机的。因而，联用药的预期相加效应，是所有药效执行单元的效应的总和，一个药效执行单元表现的药效发挥 顺序为在第一组分药A发挥效应的基础上B再沿B自身的量效曲线发挥自身剂量的效应；而另一个药效执行单元则可能表现为在第二组分药B发挥效应的基础上，A再沿着沿A自身的量效曲线发挥自身剂量的效应。
因此，两药在某一确定剂量合用时(Am和Bn)，预期相加效应值是一个范围，即为一个数集，两个预期相加效应值为该数集的边界值，分别代表所有的执行单元为百分之百的Am→Bn和百分之百的Bn→Am，中间的数值范围为不同比例的Am→Bn和Bn→Am药效执行单元药效的累积之和。预期相加效应值在该数集范围内是符合量效曲带关系，而不是现有技术中的一条直线。
第一获取模块中量效曲带的获取过程可以经过建立多条等效量效曲线而形成，而建立等效量效曲线可以通过等效量效曲线建立模块来实现。
可选地，联用药包含第一组分药A和第二组分药B，上述处理装置还包括等效量效曲线建立模块，上述等效量效曲线建立模块用于在上述第一获取模块获取联用药的预期相加效应的量效曲带的步骤之前建立多条等效量效曲线；等效量效曲线建立模块包括：第一获取单元、第二获取单元、第一查找单元、第二查找单元、第一计算单元、第三查找单元、第一转换单元、第一曲线建立单元、第四查找单元、第五查找单元、第二计算单元、第六查找单元、第二转换单元以及第二曲线建立单元；其中，第一获取单元用于获取第一组分药A的第一量效关系曲线Y＝f(x)；第二获取单元用于获取第二组分药B的第二量效关系曲线Y＝g(x)，第一查找单元用于查找第一量效关系曲线Y＝f(x)上第一组分药A在联用剂量m下的效应值f(Am)，第二查找单元用于查找第二量效关系曲线Y＝g(x)上与效应值f(Am)相同的第二组份药B的效应值g(Bm)所对应的等效剂量值Bm，第一计算单元用于计算第二组分药B的联用剂量n与等效剂量Bm的剂量和，第三查找单元用于查找得到第二量效关系曲线Y＝g(x)上第二组分药B的剂量为计量和时所对应的效应值g(Bn+Bm)，第一转换单元用于将效应值g(Bn+Bm)转换为联用药的预期相加效应值Y(Am+Bn)，第一曲线建立单元用于建立联用药的预期相加效应随第一组分药A的剂量变化的第一等效量效曲线Y(Am+Bn)＝g(Bn+Bm)；第四查找单元用于查找或计算第二量效关系曲线Y＝g(x)上第二组分药B在联用剂量Bn下的效应值g(Bn)，第五查找单元用于查找或计算第一量效关系曲线Y＝f(x)上与效应值g(Bn)相同的第一组分药A的效应值f(An)所对应的等效剂量值An，第二计算单元用于计算第一组分药A的联用剂量Am与等效剂量An的剂量和(Am+An)，第六查找单元用于查找或计算第一量效关系曲线Y＝f(x)上第一组分药A的剂量为剂量和(Am+An)时所对应的效应值f(Am+An)，第二转换单元用于将效应值f(Am+An)转换为联用药的预期相加效应值Y(Am+Bn)，第二曲线建立单元用于建立联用药的预期相加效应值随第一组分药A的剂量变化的第二等效量效曲线Y(Am+Bn)＝f(Am+An)。
上述实施例中等效量效曲线建立模块，通过第一获取单元、第二获取单元分别获取两种组分药的量效关系曲线，然后执行第一查找单元、第二查找单元和第一计算单元将第一组分药A的联用剂量下产生的效应等效兑换为第二组分药B，接着执行第三查找单元查找得到联用药的预期相加效应等效兑换为第二组分药B的剂量和时所对应的效应值；然后通过第一转换单元将第二组分药B的剂量和所对应的效应值转换为联用药的预期相加效应，最后通过执 行第一曲线建立单元建立联用药的预期相加效应随第一组分药A剂量变化的第一等效量效曲线Y(Am+Bn)＝g(Bn+Bm)；；第四查找单元用于查找或计算第二量效关系曲线Y＝g(x)上第二组分药B在联用剂量Bn下的效应值g(Bn)，第五查找单元用于查找或计算第一量效关系曲线Y＝f(x)上与效应值g(Bn)相同的第一组分药A的效应值f(An)所对应的等效剂量值An，第二计算单元用于计算第一组分药A的联用剂量Am与等效剂量An的剂量和(Am+An)，第六查找单元用于查找或计算第一量效关系曲线Y＝f(x)上第一组分药A的剂量为剂量和(Am+An)时所对应的效应值f(Am+An)，接着执行第二转换单元，将效应值f(Am+An)转换为联用药的预期相加效应值Y(Am+Bn)，最后执行第二曲线建立单元，建立联用药的预期相加效应值随第一组分药A的剂量变化的第二等效量效曲线Y(Am+Bn)＝f(Am+An)。
两种药物联用时，第一组分药A和第二组分药B并非特指某两种药，而是随组分药的种类和顺序不同而可以不断更新的。因而上述等效量效曲线建立模块中，第一组分药A和第二组分药B的量效关系曲线信息也是随药物种类和顺序的不同而随时更新的。比如，当第二组分药B更新为第一组分药A时，上述等效量效曲线建立模块所建立的是将联用药的药效等效兑换为第一组分药A的等效量效曲线。第一获取模块通过等效量效曲线建立模块分别建立各条等效量效曲线，第一获取模块通过获取所有等效量效曲线中最外围的两条等效量效曲线即可获取得到联用药的预期相加效应的量效曲带。
同理，当第一组分药A更新为(a+b)两种药的组合，而第二组分药更新为第三种药c时，或者当4种药、5种药、……、n种药联用时，只需要更新药物组合顺序，重复执行上述等效量效曲线建立模块，逐步迭代循环即可建立所有等效量效曲线，然后获取所有等效量效曲线中最外围的曲线所围成的曲带即可得到多药联用的预期相加效应的量效曲带。
可选地，上述处理装置还包括：第一计算模块以及第四输出模块；其中，第一计算模块，用于在第一输出模块将上述联用药的药效输出为协同后，计算实际量效关系曲线位于量效曲带的上方时所对应的某一目标组分药的第一剂量范围；以及第四输出模块，用于将第一剂量范围输出为某一目标组分药的协同剂量范围。
具体地，第一计算模块能够根据实际量效关系曲线与量效曲带的函数关系计算得出某一目标组分药在实际量效关系曲线与量效曲带交点处的剂量，进而根据该剂量即可计算得到位于交点上方的属于协同效应所对应的第一剂量范围。
可选地，上述处理装置还包括：第三获取模块，用于在第四输出模块将上述第一剂量范围输出为上述某一目标组分药的协同剂量范围之后，获取联用药中某一目标组分药与其余组分药之间的联用关系；第二计算模块，用于根据联用关系计算联用药中其余组分药在联用条件下的协同剂量范围；以及第五输出模块，用于输出其余组分药的协同剂量范围。
具体地，第三获取模块根据联用药中各组分要的联用关系获得联用药中某一目标组分药与其余组分药之间的联用关系。比如，当联用药为A、B和C三种时，三种药以A：B：C＝2：2：5(μg/ml+μg/ml+μg/ml)的固定比例进行联用，当A为目标组分药物时，根据三种药物联用的预期相加效应曲带与实际量效关系曲线相交位置的剂量，可以计算得到当联用药的药效 为协同时A组分药的协同剂量范围；根据A组分药与B组分药为1：1的配比关系，第三获取模块能够获取得到A组分药与B组分药的1：1的配比关系，然后第二计算模块根据第四输出模块输出的某一目标组分药的协同剂量范围计算得到组分药B的协同剂量范围。同理，根据A组分药与B组分药为2：5的配比关系，也可以得到C组分药的协同剂量范围。
同样，当联用药是以其他联用关系进行联用时，也可以根据具体联用关系的不同，得到其余组分药的协同剂量范围。比如，当A和B两种药联用，其中A以固定的1ng//ml的浓度与不同浓度(μg/ml)的B药μg/ml进行联用时，当计算得到目标药物B的协同剂量范围时，A组分药的协同剂量范围即为联用的固定剂量。
在得到各组分的协同剂量范围的基础上，将得到各组分的协同剂量范围按照联用关系进行联用，即可得到联用药的药效为协同的协同剂量范围。
可选地，处理装置还包括：第三计算模块，用于在上述第二输出模块后将上述联用药的药效输出为拮抗后，计算实际量效关系曲线位于量效曲带的下方时所对应的某一目标组分药的第二剂量范围，以及第六输出模块，用于将第二剂量范围输出为某一目标组分药的拮抗剂量范围。
具体地，第三计算模块计算实际量效关系曲线位于量效曲带的下方时所对应的某一目标组分药的第二剂量范围的方法，也可以根据实际量效关系曲线位于量效曲带相交位置处所对应的剂量，然后得出效应位于该剂量效应下方的剂量的范围，即为某一目标组分药的拮抗剂量范围。
可选地，处理装置还包括：第四获取模块，用于在上述第六输出模块将上述第二剂量范围输出为某一目标组分药的拮抗剂量范围后，获取联用药中某一目标组分药与其余组分药之间的联用关系；第四计算模块，用于根据联用关系计算联用药中其余组分药在联用条件下的拮抗剂量范围；以及第七输出模块，用于输出其余组分药的拮抗剂量范围。
具体地，上述第四获取模块和第四计算模块计算其余组分的拮抗剂量范围的方法与协同剂量范围的计算方法相同，都是根据联用药中各组分药之间的联用关系，在得到某一目标组分药的拮抗剂量范围后，按照上述协同剂量范围相同的算法得到其余组分药的拮抗剂量范围。
可选地，在第三输出模块后，处理装置还包括：第五计算模块，用于在上述第三输出模块将上述联用药的药效输出为相加后，计算实际量效关系曲线位于量效曲带范围内时所对应的某一目标组分药的第三剂量范围；以及第八输出模块，用于将第三剂量范围输出为某一目标组分药的相加剂量范围。
具体地，第五计算模块计算某一目标组分药的相加剂量范围与计算协同剂量范围的范围的方法相同，实际量效曲线与量效曲带的交点处即为联用药处于相加效应时该某以目标组分药的最小剂量和最大剂量，两剂量之间的剂量即为相加效应的剂量范围。
可选地，在第八输出模块后，处理装置还包括：第五获取模块，用于在上述第八输出模块将上述第三剂量范围输出为某一目标组分药的相加剂量范围后，获取联用药中某一目标组 分药与其余组分药之间的联用关系；第六计算模块，用于根据联用关系计算联用药中其余组分药在联用条件下的相加剂量范围；以及第九输出模块，用于输出其余组分药的相加剂量范围。
具体地，第五获取模块和第六计算模块计算其余组分药的相加剂量范围与计算协同剂量范围的方法相同，都是根据联用药中各组分药之间的联用关系，在得到上述某一目标组分药的相加剂量范围后，按照上述协同剂量范围相同的算法得到其余组分药的相加剂量范围。
可选地，第一比较模块包括：第一获取子模块，用于获取某一目标组分药在特定联用剂量下，对应的联用药在量效曲带范围内的预期相加效应的最小值和最大值；第二获取子模块，用于获取某一目标组分药在特定联用剂量下，对应的联用药在实际量效关系曲线上的实际效应值；第一计算子模块，用于计算实际效应值与预期相加效应的最小值的第一比值；第二计算子模块，用于计算实际效应值与预期相加效应的最大值的第二比值；第一标记子模块，用于将第一比值和第二比值分别标记为CId1和CId2；第一确定子模块，用于当CId1和CId2均大于1时，确定实际量效关系曲线位于量效曲带的上方；第二确定子模块，用于当CId1和CId2均小于1，确定实际量效关系曲线位于量效曲带的下方；以及第三确定子模块，用于当CId1和CId2中任一个大于等于1或者小于等于1，确定实际量效关系曲线位于量效曲带的范围内。
上述实施例便于在任一给定的剂量下，判断不同效应值水平上实际量效关系曲线与量效曲带之间的位置关系。当给予相同的剂量时，实际量效关系曲线上对应的效应值分别与量效曲带上对应的预期相加效应的最小值和最大值相比，得到基于剂量的合用指数CId1和CId2；并根据CId1和CId2同时大于1，可判断实际量效关系曲线是在量效曲带的上方；CId1和CId2同时小于1，可判断实际量效关系曲线是在量效曲带的上方；而CId1和CId2其中之一大于等于1，或者CId1和CId2其中之一小于等于1，即表明其中一个实际效应值是在预期相加效应的量效曲带上，是相加效应。
可选地，上述处理装置还包括第十一输出模块，用于在上述第一标记子模块将上述第一比值和第二比值分别标记为CId1和CId2之后，输出CId1和CId2。该模块可以根据实际应用中对合用剂量具体数值的需要进行输出。
可选地，第一比较模块包括：第三获取子模块，用于获取联用药在量效曲带上产生特定效应时所对应的某一目标组分药的剂量的最小值和最大值；第四获取子模块，用于获取联用药在实际量效关系曲线上产生特定效应时所需要的实际联用剂量；第三计算子模块，用于计算实际联用剂量与最小值的第三比值；第四计算子模块，用于计算实际联用剂量与最大值的第四比值；第二标记子模块，用于将第三比值和第四比值分别标记为CIe1和CIe2；第四确定子模块，用于当CIe1和CIe2均小于1时，确定实际量效关系曲线位于量效曲带的上方；第五确定子模块，用于当CId1和CId2均大于1时，确定实际量效关系曲线位于量效曲带的下方；以及第六确定子模块，用于当CId1和CId2中任一个大于等于1或小于等于1时，确定实际量效关系曲线位于量效曲带的范围内。
上述实施例便于在任一给定药效水平下，比较不同剂量范围内实际量效曲线与量效曲带之间的位置关系。当在某一特定的药效值时，比如ED50，在联用药的量效关系曲带上纵坐标为50处作一条平行于横坐标的直线，分别于量效曲带和实际量效曲线相较于A、B和C三点，从而得到A、B和C三点所对应的横坐标数值，假如分别为1.012、1.321和1.450。则在药效ED50处，某一目标组分药的预期相加效应的剂量最小值为1.012，最大值为1.321，而实际效应的剂量为1.450，由于CIe1＝1.450/1.012>1，CIe2＝1.450/1.321>1；表明在产生相同的药效时，实际所需要给予的某一目标组分药的剂量大于预期所需要的剂量，因而在该效应值下，实际量效关系曲线位于量效曲带的下方，药效为拮抗。同理，若CIe1和CIe2小于1，则确定实际量效关系曲线位于量效曲带的上方；若CIe1和CIe2大于1，则确定实际量效关系曲线位于量效曲带的下方；若CIe1或CIe2大于等于1，则确定实际量效关系曲线位于量效曲带的范围内。
上述实施例的位置关系比较方法由于基于量效曲带，在相同剂量条件下或者在某一给定药效水平下，基于与预期相加效应在量效曲带上的两个效应值或两个剂量值，从而能够根据联用药的合用指数更准确地定量检测联用药的药效。比如，当CIe1<1且CIe2<1时，确定实际量效关系曲线位于量效曲带的下方，联用药的药效属于协同。若CIe1和CIe2的具体数值与1相距越远，表明联用药的协同效应越强；若CIe1和CIe2的具体数值与1相距越近，表明联用药的协同效应越弱，因而能够相对定量地检测联用药的药效水平。
可选地，上述处理装置还包括第十二输出模块，用于在上述第二标记子模块将上述第三比值和第四比值分别标记为CIe1和CIe2后，输出所述CId1和CId2。该输出模块能够满足实际应用中对效应合用指数的需要。
本实施例中所提供的各个模块与方法实施例对应步骤所提供的使用方法相同、应用场景也可以相同。当然，需要注意的是，上述模块涉及的方案可以不限于上述实施例中的内容和场景，且上述模块可以运行在计算机终端或移动终端，可以通过软件或硬件实现。
本申请的实施例还可以提供一种计算机终端，该计算机终端可以是计算机终端群中的任意一个计算机终端设备。可选地，在本实施例中，上述计算机终端也可以替换为移动终端等终端设备。
可选地，计算机终端可以包括：一个或多个处理器、存储器以及传输装置。
其中，存储器可用于存储软件程序以及模块，如本申请实施例中的联用药药效处理方法和装置对应的程序指令/模块，处理器通过运行存储在存储器内的软件程序以及模块，从而执行各种功能应用以及数据处理，即实现上述的联用药药效处理方法。存储器可包括高速随机存储器，还可以包括非易失性存储器，如一个或者多个磁性存储装置、闪存、或者其他非易失性固态存储器。在一些实例中，存储器可进一步包括相对于处理器远程设置的存储器，这些远程存储器可以通过网络连接至某一终端。上述网络的实例包括但不限于互联网、企业内部网、局域网、移动通信网及其组合。
处理器可以通过传输装置调用存储器存储的信息及应用程序，以执行下述步骤：获取联用药的预期相加效应的量效曲带，量效曲带由多条等效量效曲线中最外围的两条围成，每条 等效量效曲线是指以联用药中的某一目标组分药的剂量为横坐标，以联用药等效兑换为每一组分药所获得的预期相加效应为纵坐标而建立的曲线；等效兑换按照所获取的联用药中各组分药的用药顺序进行等效兑换；获取联用药的实际效应值随联用药中的某一目标组分药的剂量变化形成的实际量效关系曲线；比较实际量效关系曲线与量效曲带的位置关系，以及当实际量效关系曲线位于量效曲带的上方时，将联用药的药效输出为协同；当实际量效关系曲线位于量效曲带的下方时，将联用药的药效输出为拮抗；当实际量效关系曲线位于量效曲带范围内时，将联用药的药效输出为相加。
可选地，联用药包括第一组分药A和第二组分药B，上述处理方法在获取上述联用药的预期相加效应的量效曲带的步骤之前，还包括建立多条等效量效曲线的步骤，其中，建立多条等效量效曲线形成的步骤包括：获取第一组分药A的第一量效关系曲线Y＝f(x)；获取第二组分药B的第二量效关系曲线Y＝g(x)；查找第一量效关系曲线Y＝f(x)上第一组分药A在联用剂量m下的效应值f(Am)；查找第二量效关系曲线Y＝g(x)上与效应值f(Am)相同的第二组份药B的效应值g(Bm)所对应的等效剂量值Bm；计算第二组分药B的联用剂量n与等效剂量Bm的剂量和；查找得到第二量效关系曲线Y＝g(x)上第二组分药B的剂量为计量和时所对应的效应值g(Bn+Bm)；将效应值g(Bn+Bm)转换为联用药的预期相加效应值Y(Am+Bn)；建立联用药的预期相加效应随第一组分药A的剂量变化的第一等效量效曲线Y(Am+Bn)＝g(Bn+Bm)；查找或计算第一量效关系曲线Y＝f(x)上与效应值g(Bn)相同的第一组分药A的效应值f(An)所对应的等效剂量值An，计算第一组分药A的联用剂量Am与等效剂量An的剂量和(Am+An)，查找或计算第一量效关系曲线Y＝f(x)上第一组分药A的剂量为剂量和(Am+An)时所对应的效应值f(Am+An)，将效应值f(Am+An)转换为联用药的预期相加效应值Y(Am+Bn)，建立联用药的预期相加效应值随第一组分药A的剂量变化的第二等效量效曲线Y(Am+Bn)＝f(Am+An)。
本申请的上述处理方法通过基于联用药的预期相加效应的量效曲带，与联用药的实际量效曲线进行比对，然后通过实际量效曲线与量效曲带的位置关系来判断联用药的药效。由于量效曲带符合药物的量效关系以及药物合用的药效学基本特征，该实施例的药效处理方法综合了多种药物在联用时的用药次序的不同以及不同药物量效关系的不同对联用药药效的影响，不仅能够实现对多种(两种及两种以上)药物联用时的药效进行检测，而且能够实现定量检测。这种处理方法不仅解决了现有技术中多药联用时的药效无法准确检测的问题，而且所检测得到的联用药的药效能够广泛应用于复方药的研发、毒理学研究以及环境评价中。此外，还能够定量计算多个药物、在不同的联用方式下，产生协同、相加和拮抗的剂量范围以及其他药物联用的相关指标。
本申请的实施例还提供了一种存储介质。可选地，在本实施例中，上述存储介质可以用于保存上述实施例所提供的联用药药效处理方法所执行的程序代码。
可选地，在本实施例中，上述存储介质可以位于计算机网络中计算机终端群中的任意一个计算机终端中，或者位于移动终端群中的任意一个移动终端中。
可选地，在本实施例中，存储介质被设置为存储用于执行以下步骤的程序代码：
获取联用药的预期相加效应的量效曲带，量效曲带由多条等效量效曲线中最外围的两条围成，每条等效量效曲线是指以联用药中的某一目标组分药的剂量为横坐标，以联用药等效兑换为每一组分药所获得的预期相加效应为纵坐标而建立的曲线；等效兑换按照所获取的联用药中各组分药的用药顺序进行等效兑换；获取联用药的实际效应值随联用药中的某一目标组分药的剂量变化形成的实际量效关系曲线；比较实际量效关系曲线与量效曲带的位置关系，以及当实际量效关系曲线位于量效曲带的上方时，将联用药的药效输出为协同；当实际量效关系曲线位于量效曲带的下方时，将联用药的药效输出为拮抗；当实际量效关系曲线位于量效曲带范围内时，将联用药的药效输出为相加。
可选地，存储介质被设置为存储还用于执行以下步骤的程序代码：每条等效量效曲线形成的步骤包括：获取第一组分药A的第一量效关系曲线Y＝f(x)；获取第二组分药B的第二量效关系曲线Y＝g(x)；查找第一量效关系曲线Y＝f(x)上第一组分药A在联用剂量m下的效应值f(Am)；查找第二量效关系曲线Y＝g(x)上与效应值f(Am)相同的第二组份药B的效应值g(Bm)所对应的等效剂量值Bm；计算第二组分药B的联用剂量n与等效剂量Bm的剂量和；查找得到第二量效关系曲线Y＝g(x)上第二组分药B的剂量为计量和时所对应的效应值g(Bn+Bm)；将效应值g(Bn+Bm)转换为联用药的预期相加效应值Y(Am+Bn)；建立联用药的预期相加效应随第一组分药A的剂量变化的第一等效量效曲线Y(Am+Bn)＝g(Bn+Bm)；查找或计算第一量效关系曲线Y＝f(x)上与效应值g(Bn)相同的第一组分药A的效应值f(An)所对应的等效剂量值An，计算第一组分药A的联用剂量Am与等效剂量An的剂量和(Am+An)，查找或计算第一量效关系曲线Y＝f(x)上第一组分药A的剂量为剂量和(Am+An)时所对应的效应值f(Am+An)，将效应值f(Am+An)转换为联用药的预期相加效应值Y(Am+Bn)，建立联用药的预期相加效应值随第一组分药A的剂量变化的第二等效量效曲线Y(Am+Bn)＝f(Am+An)。
本申请的上述实施例方案中，通过基于联用药的预期相加效应的量效曲带，与联用药的实际量效曲线进行比对，然后通过实际量效曲线与量效曲带的位置关系来判断联用药的药效。由于量效曲带符合药物的量效关系以及药物合用的药效学基本特征，该实施例的药效处理方法综合了多种药物在联用时的用药次序的不同以及不同药物量效关系的不同对联用药药效的影响，不仅能够实现对多种(两种及两种以上)药物联用时的药效进行检测，而且能够实现定量检测。这种处理方法不仅解决了现有技术中多药联用时的药效无法准确检测的问题，而且所检测得到的联用药的药效能够广泛应用于复方药的研发、毒理学研究以及环境评价中。此外，还能够定量计算多个药物、在不同的联用方式下，产生协同、相加和拮抗的剂量范围以及其他药物联用的相关指标。
上述本申请实施例序号仅仅为了描述，不代表实施例的优劣。
在本申请的上述实施例中，对各个实施例的描述都各有侧重，某个实施例中没有详述的部分，可以参见其他实施例的相关描述。
在本申请所提供的几个实施例中，应该理解到，所揭露的技术内容，可通过其它的方式实现。其中，以上所描述的装置实施例仅仅是示意性的，例如所述单元的划分，仅仅为一种逻辑功能划分，实际实现时可以有另外的划分方式，例如多个单元或组件可以结合或者可以 集成到另一个系统，或一些特征可以忽略，或不执行。另一点，所显示或讨论的相互之间的耦合或直接耦合或通信连接可以是通过一些接口，单元或模块的间接耦合或通信连接，可以是电性或其它的形式。
所述作为分离部件说明的单元可以是或者也可以不是物理上分开的，作为单元显示的部件可以是物理单元或者也可以不是物理单元，即可以位于一个地方，或者也可以分布到多个网络单元上。可以根据实际的需要选择其中的部分或者全部单元来实现本实施例方案的目的。
另外，在本申请各个实施例中的各功能单元可以集成在一个处理单元中，也可以是各个单元单独物理存在，也可以两个或两个以上单元集成在一个单元中。上述集成的单元既可以采用硬件的形式实现，也可以采用软件功能单元的形式实现。
所述集成的单元如果以软件功能单元的形式实现并作为独立的产品销售或使用时，可以存储在一个计算机可读取存储介质中。基于这样的理解，本申请的技术方案本质上或者说对现有技术做出贡献的部分或者该技术方案的全部或部分可以以软件产品的形式体现出来，该计算机软件产品存储在一个存储介质中，包括若干指令用以使得一台计算机设备(可为个人计算机、服务器或者网络设备等)执行本申请各个实施例所述方法的全部或部分步骤。而前述的存储介质包括：U盘、只读存储器(ROM，Read-Only Memory)、随机存取存储器(RAM，Random Access Memory)、移动硬盘、磁碟或者光盘等各种可以存储程序代码的介质。
下面结合具体的实施例来进一步说明本发明的有益效果。
实施例1：两药合用的药效的处理方法
1)药物NX和药物TX按固定比例合用；
2)药物TX固定剂量，与不同剂量药物NX联合应用。
题目：硝羟基化合物(NX)为抗感染药，近年发现具有靶向抗癌活性，SFDA已批准进入临床试验；紫杉醇(TX)是临床常用抗癌药物。以NX/TX联合应用，MTT法检测抑制人肝癌细胞HepG2生长。阐述定量处理协同/相加/拮抗的相关指标的方法，为新抗癌复方研发提供参考。
第一部分NX/TX固定比例NX:TX＝1:1(μg/ml+ng/ml)的两药合用的药效处理方法
步骤1制作各单药和合用组各成员剂量水平的量效关系表，拟合各自的量效关系曲线方程。其中，硝基化合物(NX)和紫杉醇(TX)、单药的量效关系数据，NX+TX以固定比例合用(1/1，μg/ml/ng/ml)、TX固定浓度(2ng/ml)+不同浓度NX合用的量效关系数据，见表1。
表1：硝羟基化合物(NX)和紫杉醇(TX)单用及合用的量效关系数据
Figure PCTCN2016097514-appb-000010
Figure PCTCN2016097514-appb-000011
绘制药物NX和药物TX单用、药物合用组中的药物NX的量效曲线图，如图3A、图3B、图3C和图3D所示。
用logistic程序分别拟合出各图的量效关系方程，分别为：
单用药物NX：Y＝(4.3188-94.209)/{1+(X/1.9981)^3.0815}+94.209，其量效关系曲线如图3A所示，
单用药物TX：Y＝(0.8779-92.1626)/{1+(X/2.8494)^1.7569}+92.1626，其量效关系曲线如图3B所示，
固定比例合用组中NX：Y＝(15.8595-94.9017)/{1+(X/1.7190)^2.4490}+94.9017，其实际量效关系曲线如图3C所示，
TX固定浓度合用组中NX：Y＝(7.294-94.22)/{1+(X/1.569^3.1080}+94.22，其实际量效关系曲线如图3D所示；
步骤2剂量序贯兑换，计算合用条件下构成预期相加药效曲带的各条量效关系数据
直接计算法：对现有几个合用剂量点进行评价。
计算NX/TX固定比例下，对现有的几个合用组剂量，序贯进行等效剂量兑换后合并剂量值，具体见表2。
表2：硝羟基化合物(NX)+紫杉醇(TX)按固定比例合用，以NX为目标药的序贯进行等效剂量兑换后，预期相加效应的计算表
Figure PCTCN2016097514-appb-000012
Figure PCTCN2016097514-appb-000013
附：表2中的计算公式：①NX：Y＝(4.3188-94.209)/{1+(X/1.9981)^3.0815}+94.209；②TX：Y＝(0.8779-92.1626)/{1+(X/2.8494)^1.7569}+92.1626。
表2中各栏目数值计算说明：(3)栏：将(2)栏数据用公式②算出；(4)栏：将(3)栏用公式①算出；(5)栏：(1)栏+(4)栏；(6)栏：将(5)栏数据用公式①算出。
表3硝羟基化合物(NX)+紫杉醇(TX)按固定比例合用，以TX为目标药的序贯进行等效剂量兑换后，预期相加效应的计算表
Figure PCTCN2016097514-appb-000014
附：表3中计算公式：①NX：Y＝(4.3188-94.209)/{1+(X/1.9981)^3.0815}+94.209；②TX：Y＝(0.8779-92.1626)/{1+(X/2.8494)^1.7569}+92.1626。
各栏目数值计算说明：(7)栏：将(1)栏数据用公式①算出；(8)栏：将(7)数据用公式②算出；(9)栏：(2)栏+(8)栏；(10)栏：将(9)栏数据用公式②算出；“-”：超出了TX的量效范围。
以合用组的NX各剂量水平为横坐标，以各预期相加效应值为纵坐标作图，构成预期等效相加效应的量效曲带。同时在该图上作出合用组的实际效应曲线，如图4所示。从图4中可以看出粗线条的两条曲线围成的区域为预期相加效应的量效曲带，而细线条的曲线为合用组实际量效关系曲线，该曲线与相加效应区带相交汇。即合用组剂量范围中，有协同部分、有相加部分、有拮抗部分。
根据上述图4，列出合用组各剂量水平的预期相加效应并计算基于剂量的合用指数(CId)，具体见表4。
表4：
Figure PCTCN2016097514-appb-000015
Figure PCTCN2016097514-appb-000016
各栏目数值计算说明：(3)栏：来自表2；(4)栏：来自表3；(5)栏：来自表1；(6)栏：(5)栏数据/(3)栏数据；(7)栏：(5)栏数据/(4)栏目数据；(8)栏：标准见前面CId计算。
直接计算法，可大致判断协同、相加和拮抗的状况。能对现有的合用组剂量水平进行判断，但横坐标每个剂量水平间差距较大，只能大概估算各种药效的剂量范围，不能精确确定各部分的剂量。可判断是否进行精确计算的必要性。如果需要精确计算各种药效的剂量范围时，需要在每个剂量水平间，插入几个中间剂量值，根据已确立的量效关系函数，序贯进行剂量兑换后，计算出预期相加效应值，再进行函数拟合。
精确计算法：
为提高合用组预期相加效应曲带的拟合精度，可根据需求，在每个合用剂量之间插入数个中间剂量值，本组数据每个剂量间隔设置了3～4个插值，如0.5+0.5与1+1之间，增加了0.6+0.6，0.7+0.7，0.8+0.8，0.9+0.9等，如表5所示。
第一步，以NX为目标药物，将TX进行等效剂量兑换后，合并等效剂量，用单用NX的量效曲线方程，计算预期相加效应值，见表4的(3)、(4)、(5)、(6)栏目数据。
表5：硝羟基化合物(NX)+紫杉醇(TX)按固定比例合用，以NX为目标药的序贯进行等效剂量兑换后，预期相加效应的计算表。
Figure PCTCN2016097514-appb-000017
Figure PCTCN2016097514-appb-000018
计算公式：①NX：Y＝(4.3188-94.209)/{1+(X/1.9981)^3.0815}+94.209；②TX：Y＝(0.8779-92.1626)/{1+(X/2.8494)^1.7569}+92.1626。各栏目数值计算说明：(3)栏：将(2)栏数据用公式②算出；(4)栏：将(3)栏用公式①算出；(5)栏：(1)栏+(4)栏；(6)栏：将(5)栏数据用公式①算出。
第二步，以TX为目标药物，将NX进行等效剂量兑换后，合并等效剂量，用单用TX的量效曲线方程，计算预期相加效应值，见表6的(7)、(8)、(9)、(10)栏目数据。
表6：硝羟基化合物(NX)+紫杉醇(TX)按固定比例合用，以TX为目标药的序贯进行等效剂量兑换后，预期相加效应的计算表。
Figure PCTCN2016097514-appb-000019
Figure PCTCN2016097514-appb-000020
计算公式：①NX：Y＝(4.3188-94.209)/{1+(X/1.9981)^3.0815}+94.209；②TX：Y＝(0.8779-92.1626)/{1+(X/2.8494)^1.7569}+92.1626；。
各栏目数值计算说明：将(5)栏数据用公式①算出。(7)栏：将(1)栏数据用公式①算出；(8)栏：将(7)数据用公式②算出；(9)栏：(2)栏+(8)栏；(10)栏：将(9)栏数据用公式②算出；“-”：超出了TX的量效范围。
步骤3重构量效曲线和拟合曲线方程
以合用组的NX各剂量水平为横坐标，以各预期相加效应值和拟合的实际效应值[(6)栏目、(10)栏目]为纵坐标作图，构成预期等效相加效应的量效曲带。同时在该图上作出方程式③NX+TX：Y＝(15.8595-94.9017)/{1+(X/1.7190)^2.4490}+94.9017的实际量效曲线，如图5所示。
将合用组中NX剂量与NX为目标药的预期相加效应值进行量效方程拟合。合用组中NX剂量与TX为目标药的预期相加效应值进行量效方程拟合，得到围成预期相加效应的量效曲带的两条等效量效曲线，等效量效曲线的方程分别为：
以NX为目标药：YNX＝(-6.572-94.33)/{1+(X/0.9231)^2.452}+94.33；
以TX为目标药：YTX＝(8.534-93.93)/{1+(X/1.439)^2.478}+93.93；
步骤4比较合用组预期相加效应的量效曲带和实际量效曲线的位置关系，计算相关指标。
[1]目测结果：从图5可以看出，合用剂量点0.5+0.5(μg/ml+ng/ml)位于量效曲带上方，呈现协同效应；合用剂量点1+1、2+2、4+4(μg/ml+ng/ml)位于量效曲带下方，呈现拮抗效应。合用剂量点8+8、16+16(μg/ml+ng/ml)，超出了TX为目标的预期相加效应曲线范围，在合用剂量点6+6(μg/ml+ng/ml)以后，预期相加效应的量效关系，仅为NX为目标的预期相加效应曲线，合用剂量点8+8(μg/ml+ng/ml)为拮抗、16+16(μg/ml+ng/ml)为协同。
[2]计算协同、相加和拮抗的剂量范围
将上面两个方程式，分别与实际效应的量效方程解方程组，即：
方程组1：
Y＝(-6.572-94.33)/{1+(X/0.9231)^2.452}+94.33
Y＝(15.8595-94.9017)/{1+(X/1.7190)^2.4490}+94.9017
方程组2：
Y＝(8.534-93.93)/{1+(X/1.439)^2.478}+93.93
Y＝(15.8595-94.9017)/{1+(X/1.7190)^2.4490}+94.9017
解方程组1，得出：X1＝0.6344，Y1＝22.1901；X2＝11.2124，Y2＝94.1093；
解方程组2，得出：X＝0.9359，Y＝30.4090
得出相加效应的NX剂量界限是0.6344和0.9359μg/ml，根据NX与TX的组合关系(1:1)，很容易得到TX相加效应的剂量范围。NX和TX在共同的效应范围内，
协同效应剂量范围(NX+TX)：[0.5+0.5，0.6344+0.6344)μg/ml+ng/ml；
相加效应剂量范围(NX+TX)：[0.6344+0.6344，0.9359+0.9359]μg/ml+ng/ml；
拮抗效应剂量范围(NX+TX)：(0.9359+0.9359，6+6]μg/ml+ng/ml。
合用组实际效应量效曲线中属于相加效应的范围是：22.1901％～30.4090％。
NX和TX在共同的效应范围之外，还有一个相加效应点(NX+TX：11.2124+11.2124，μg/ml+ng/m)，可以看出，合用剂量点8+8(μg/ml+ng/ml)在此点下方，为拮抗；16+16(μg/ml+ng/ml)，在此点上方为协同。
[3]计算CId
从表5和表6可以看出，剂量点0.5+0.5(μg/ml+ng/ml)的预期相加效应值分别为11.5和14.2，实际观测值为19.7(表4)。CId1为19.7/14.2＝1.3873>1，CId2为19.7/11.5＝1.7130>1，协同。剂量点1+1(μg/ml+ng/ml)的预期相加效应值分别为48.7和33.2，实际观测值为23.8。CId1为23.8/48.7＝0.4887<1，CId2为23.8/33.2＝0.7168<1，拮抗。同理可推算出剂量点2+2(μg/ml+ng/ml)，4+4(μg/ml+ng/ml)，CId1和CId2均<1，拮抗。剂量点8+8(μg/ml+ng/ml)和16+16(μg/ml+ng/ml)CId的计算略。
[4]计算CIe
可选定任一药效水平，如：ED50，或可根据需要选取药效水平。在合用组量效关系曲线图上纵坐标为50处，作一平行于横轴的直线，分别与等效量效曲带和实际量效曲线交点于A、B、C点，如图6所示，分别得到横坐标点为1.0196、1.4059、1.5370。在药效ED50处，预期相加效应的剂量范围点(NX+TX)为1.0196+1.0196(μg/ml+ng/ml)和1.4059+1.4059(μg/ml+ng/ml)，实际效应的剂量点(NX+TX)为1.5370+1.5370(μg/ml+ng/ml)，位于量效曲带的下方。
计算CIe1和CIe2，分别为CIe1＝1.5370/1.4059＝1.0932>1，CIe2＝1.5370/1.0196＝1.5074>1，提示为拮抗。
第二部分TX固定剂量(2ng/ml)与不同浓度NX的两药合用的计算
步骤1制作各单药和合用组各成员剂量水平的量效关系表，拟合各自的量效关系曲线方程
硝羟基化合物(NX)和紫杉醇(TX)、单药的量效关系数据，TX固定浓度(2ng/ml)+不同浓度NX合用的量效关系数据，见前表1。
绘制药物NX和药物TX单用、药物合用组中的药物NX的量效曲线图，如图3A、图3B以及图3D所示。用logistics程序分别拟合出各自的量效关系方程，分别为：
单用药物NX：Y＝(4.3188-94.209)/{1+(X/1.9981)^3.0815}+94.209
单用药物TX：Y＝(0.8779-92.1626)/{1+(X/2.8494)^1.7569}+92.1626
TX固定浓度合用组中NX：Y＝(7.294-94.22)/{1+(X/1.569^3.1080}+94.22
步骤2剂量序贯兑换，计算合用条件下构成预期相加药效曲带的各个量效关系数据
精确计算法：计算TX固定剂量2ng/ml下，序贯进行等效剂量兑换后合并剂量值。为提高预期相加效应曲带的拟合精度，可在每个合用剂量之间插入数个中间剂量值，本组数据每个剂量间隔设置了4个插值，如0.5+0.5与1+1之间，增加了0.6+0.6，0.7+0.7，0.8+0.8，0.9+0.9等。
第一步，以NX为目标药物，将TX进行等效剂量兑换后，合并等效剂量，用单用NX的量效曲线方程，计算预期相加效应值，见表7的(3)、(4)、(5)、(6)栏目数据。
表7硝羟基化合物(NX)+紫杉醇(TX)按固定比例合用，以NX为目标药的序贯进行等效剂量兑换后，预期相加效应的计算表。
Figure PCTCN2016097514-appb-000021
Figure PCTCN2016097514-appb-000022
计算公式：①NX：Y＝(4.3188-94.209)/{1+(X/1.9981)^3.0815}+94.209；②TX：Y＝(0.8779-92.1626)/{1+(X/2.8494)^1.7569}+92.1626。各栏目数值计算说明：(3)栏：将(2)栏数据用公式②算出；(4)栏：将(3)栏用公式①算出；(5)栏：(1)栏+(4)栏；(6) 栏：将(5)栏数据用公式①算出。
第二步，以TX为目标药物，将NX进行等效剂量兑换后，合并等效剂量，用单用TX的量效曲线方程，计算预期相加效应值，见表8的(7)、(8)、(9)、(10)栏目数据。
表8紫杉醇(TX)固定浓度+硝羟基化合物(NX)不同比例合用，以TX为目标药的序贯进行等效剂量兑换后，预期相加效应的计算表。
Figure PCTCN2016097514-appb-000023
Figure PCTCN2016097514-appb-000024
计算公式：①NX：Y＝(4.3188-94.209)/{1+(X/1.9981)^3.0815}+94.209；②TX：Y＝(0.8779-92.1626)/{1+(X/2.8494)^1.7569}+92.1626；。各栏目数值计算说明：将(5)栏数据用公式①算出。(7)栏：将(1)栏数据用公式①算出；(8)栏：将(7)数据用公式②算出；(9)栏：(2)栏+(8)栏；(10)栏：将(9)栏数据用公式②算出；“-”：超出了TX的量效范围。
步骤3重构量效曲线和拟合曲线方程
以合用组的NX各剂量水平为横坐标，以各预期相加效应值和拟合的实际效应值[(6)栏目、(10)栏目]为纵坐标作图，构成如图7所示的预期等效相加效应的量效曲带。同时在该图上作出方程式③NX+TX(固定)：Y＝(7.294-94.22)/{1+(X/1.569^3.1080}+94.22的实际量效曲线。
将合用组中NX剂量与NX为目标药的预期相加效应值进行量效方程拟合。合用组中NX剂量与TX为目标药的预期相加效应值进行量效方程拟合，得到围成预期相加效应量效曲带的两条等效量效曲线，其曲线方程分别为：
以NX为目标药：YNX＝(42.46-94.7)/{1+(X/1.136)^1.892}+94.7；
以TX为目标药：YTX＝(39.95-94.91)/{1+(X/1.976)^2.41}+94.91。
步骤4比较合用组预期相加效应量效曲带和实际量效曲线的位置关系，计算相关指标
[1]目测结果：从图7可以看出，合用剂量点0.5+2、1+2、2+2(μg/ml+ng/ml)位于量效曲带下方，呈现拮抗效应；合用剂量点4+2(μg/ml+ng/ml)位于量效曲带内，呈现相加效应；合用剂量点8+2(μg/ml+ng/ml)在线上；16+2(μg/ml+ng/ml)位于量效曲带范围上方，呈现协同效应。
[2]计算协同、相加和拮抗的剂量范围
从图7中可以看出，实际效应量效曲线与量效曲带下方有明显交点，与上方曲线似乎也有交点，因此，需求解两个方程组。
方程组1
YNX＝(42.46-94.7)/{1+(X/1.136)^1.892}+94.7
Y＝(7.294-94.22)/{1+(X/1.569)^3.1080}+94.22
方程组2：
YTX＝(39.95-94.91)/{1+(X/1.976)^2.41}+94.91
Y＝(7.294-94.22)/{1+(X/1.569)^3.1080}+94.22
解方程组1，得出：X＝4.5777；Y＝91.2101；
解方程组2，得出：X＝2.1229；Y＝69.7986。
得出相加效应的NX剂量界限是2.1229～4.5777μg/ml，根据NX与TX的组合关系(固定剂量2ng/ml)，很容易得到TX相加效应的剂量范围。NX和TX在共同的效应范围内，
协同效应剂量范围(NX+TX)：[0.5+2，2.1229+2)μg/ml+ng/ml；
相加效应剂量范围(NX+TX)：[2.1229+2，4.5777+2]μg/ml+ng/ml；
拮抗效应剂量范围(NX+TX)：(4.5777+2，6+2]μg/ml+ng/ml。
合用组实际效应量效曲线中属于相加效应的范围是69.7986％～91.2101％
在共同效应区以外的合用剂量点，合用剂量点8+2(μg/ml+ng/ml)的预期相加效应值的计算，遵循YNX＝(42.46-94.7)/{1+(X/1.136)^1.892}+94.7，代入X＝8，得到93.431，而实际观测值为92.9，为拮抗。合用剂量点16+2(μg/ml+ng/ml)的预期相加效应值为94.1563，而实际观测值为96.1，为协同。
[3]计算CId和CIe，具体计算方法如前述，此处略过。
实施例2：三药合用的药效检测方法
题目：化疗药在肺癌治疗中的应用方案有多种，这些方案中的化疗药主要包括以下：从化疗药种类上属于拓扑异构酶抑制剂、微管抑制剂、代谢抑制剂、烷化剂等四类。从这四类药物中依次选择一种代表药物，分别为依托泊苷(A)、长春新碱(B)、5-氟尿嘧啶(C)、阿霉素(D)，任意三种联合应用方案，MTT法检测对人肺癌细胞H460细胞株生长的抑制效应。三种方案依次为A+B+C，A+B+D，A+C+D，B+C+D等四种联合用药组合，定量评价其协同、相加和拮抗效应。
A+B+C组合：A:B:C＝12.5:2:45(μg/ml+μg/ml+μg/ml)；
A+B+D组合：A:B:D＝12.5:2:4(μg/ml+μg/ml+μg/ml)
A+C+D组合：A:C:D＝12.5:45:4(μg/ml+μg/ml+μg/ml)
B+C+D组合：B:C:D＝2:45:4(μg/ml+μg/ml+μg/ml)
第一部分依托泊苷(A)、长春新碱(B)和5-氟尿嘧啶(C)合用，在固定比例A:B:C＝12.5:2:45(μg/ml+μg/ml+μg/ml)的三药合用的计算
步骤1制作各单药和合用组各成员剂量水平的量效关系表，拟合各自的量效关系曲线方程
依托泊苷(A)、长春新碱(B)和5-氟尿嘧啶(C)，单药的量效关系数据和合用A:B:C＝12.5:2:45(μg/ml+μg/ml+μg/ml)的量效关系数据，见表9和表10。
表9依托泊苷(A)、长春新碱(B)和5-氟尿嘧啶(C)，单用的量效关系数据表。
Figure PCTCN2016097514-appb-000025
表10依托泊苷(A)、长春新碱(B)和5-氟尿嘧啶(C)，三药合用的量效关系数据表。
Figure PCTCN2016097514-appb-000026
绘制三药依托泊苷(A)、长春新碱(B)和5-氟尿嘧啶(C)三种单药的量效曲线图，分别如图8A、图8B、图8C所示，并绘制药物合用组中，合用预期相加效应随依托泊苷(A)剂量变化的实际量效关系曲线图，如图8D所示。
用logistics程序分别拟合出各自的量效关系方程，分别为：
单用A：Y＝(-5.003-99.54)/{1+(X/2.269)^0.3073}+99.54
单用B：Y＝(4.901-63.00)/{1+(X/0.03216)^1.385}+63.00
单用C：Y＝(-2.944-86.77)/{1+(X/1.182)^0.8216}+86.77
三药合用中A：Y＝(17.01-84.13)/{1+(X/0.1083)^0.6546}+84.13
步骤2剂量序贯兑换，计算合用条件下构成预期相加药效曲带的各个量效关系数据
计算依托泊苷(A)、长春新碱(B)和5-氟尿嘧啶(C)，在固定比例条件下，序贯进行等效剂量兑换后合并剂量值。
首先序贯进行A+B、A+C、B+C等两药组合的等效剂量兑换，然后序贯进行(A+B)+C、(A+C)+B、(B+C)+A的等效剂量兑换。三药合用预期相加效应值的表达式为
Figure PCTCN2016097514-appb-000027
其中
Figure PCTCN2016097514-appb-000028
表示数集内单元的函数值，须按照从低(Low)到高(High)排列，而
Figure PCTCN2016097514-appb-000029
表示A、B和C三药联用的预期相加效应值为(A+B)+C，(A+C)+B，(B+C)+A三种组合得到的效应值中由最低值到最高值之间的集合。
(一)(A+B)+C的等效剂量序贯兑换
第一步，以A为目标药物，将B进行等效剂量兑换后(Ab)，合并等效剂量(A+Ab)，用单用A的量效曲线方程，计算预期相加效应值，见表11的(3)、(4)、(5)、(6)栏目数据。
表11依托泊苷(A)、长春新碱(B)按固定比例合用，以依托泊苷(A)为目标药的序贯进行等效剂量兑换后，预期相加效应的计算表。
Figure PCTCN2016097514-appb-000030
计算公式：①单用A：Y＝(-5.003-99.54)/{1+(X/2.269)^0.3073}+99.54；②单用B：Y＝(4.901-63.00)/{1+(X/0.03216)^1.385}+63.00。各栏目数值计算说明：(3)栏：将(2)栏数据用公式②算出；(4)栏：将(3)栏用公式①算出；(5)栏：(1)栏+(4)栏；(6) 栏：将(5)栏数据用公式①算出。
第二步，以B为目标药物，将A进行等效剂量兑换后(Ba)，合并等效剂量(B+Ba)，用单用B的量效曲线方程，计算预期相加效应值，见表12的(7)、(8)、(9)、(10)栏目数据。
表12依托泊苷(A)、长春新碱(B)按固定比例合用，以长春新碱(B)为目标药的序贯进行等效剂量兑换后，预期相加效应的计算表。
Figure PCTCN2016097514-appb-000031
Figure PCTCN2016097514-appb-000032
计算公式：①单用A：Y＝(-5.003-99.54)/{1+(X/2.269)^0.3073}+99.54；②单用B：Y＝(4.901-63.00)/{1+(X/0.03216)^1.385}+63.00。各栏目数值计算说明：(7)栏：将(1)栏数据用公式①算出；(8)栏：将(7)数据用公式②算出；(9)栏：(2)栏+(8)栏；(10) 栏：将(9)栏数据用公式②算出。
第三步，以(A+B)＝(A+Ab)为目标药物，将C进行等效剂量兑换(Ac)，合并等效剂量[(A+Ab)+Ac]，用单用A量效曲线方程，计算预期相加效应值，见表13的(11)、(12)、(13)、(14)栏目数据。
表13依托泊苷与长春新碱组合(A+B)、5-氟尿嘧啶(C)按固定比例合用，以(A+Ab)为目标药的序贯进行等效剂量兑换后，预期相加效应的计算表。
Figure PCTCN2016097514-appb-000033
计算公式：①组合(A+B)＝(A+Ab)：Y＝(-5.003-99.54)/{1+(X/2.269)^0.3073}+99.54；②单用C：Y＝(-2.944-86.77)/{1+(X/1.182)^0.8216}+86.77。各栏目数值计算说明：(11)栏：将(2) 栏数据用公式②算出；(12)栏：将(11)栏用公式①算出；(13)栏：(1)栏+(12)栏；(14)栏：将(13)栏数据用公式①算出。
第四步，以(A+B)＝(B+Ba)为目标药物，将C进行等效剂量兑换(Bc)，合并等效剂量[(B+Ba)+Bc]，用单用B量效曲线方程，计算预期相加效应值，见表14的(15)、(16)、(17)、(18)栏目数据。
表14依托泊苷与长春新碱组合(A+B)、5-氟尿嘧啶(C)按固定比例合用，以(B+Ba)为目标药的序贯进行等效剂量兑换后，预期相加效应的计算表
Figure PCTCN2016097514-appb-000034
计算公式：①组合(A+B)＝(B+Bb)：Y＝(4.901-63.00)/{1+(X/0.03216)^1.385}+63.00；②单用C：Y＝(-2.944-86.77)/{1+(X/1.182)^0.8216}+86.77。各栏目数值计算说明：(15)栏：将(2)栏数据用公式②算出；(16)栏：将(15)栏用公式①算出；(17)栏：(1)栏+(16)栏；(18)栏：将(17)栏数据用公式①算出。
第五步，以C为目标药物，将(A+B)＝(A+Ab)进行等效剂量兑换(C(A+Ab))，合并等效剂量[C+C(A+Ab)]，用单用C量效曲线方程，计算预期相加效应值，见表15的(19)、(20)、(21)、(22)栏目数据。
表15依托泊苷与长春新碱组合(A+B)、5-氟尿嘧啶(C)按固定比例合用，以C为目标药的序贯进行等效剂量兑换后，预期相加效应的计算表。
Figure PCTCN2016097514-appb-000035
Figure PCTCN2016097514-appb-000036
计算公式：①组合(A+B)＝(A+Ab)：Y＝(-5.003-99.54)/{1+(X/2.269)^0.3073}+99.54；②单用C：Y＝(-2.944-86.77)/{1+(X/1.182)^0.8216}+86.77。各栏目数值计算说明：(19)栏：将(1)栏数据用公式①算出；(20)栏：将(19)栏用公式②算出；(21)栏：(1)栏+(12)栏；(22)栏：将(13)栏数据用公式②算出。
第六步，以C为目标药物，将(A+B)＝(B+Ba)进行等效剂量兑换(C(B+Ba))，合并等效剂量[C+C(B+Ba)]，用单用C量效曲线方程，计算预期相加效应值，见表16的(23)、(24)、(25)、(26)栏目数据。
表16依托泊苷与长春新碱组合(A+B)、5-氟尿嘧啶(C)按固定比例合用，以C为目标药的序贯进行等效剂量兑换后，预期相加效应的计算表。
Figure PCTCN2016097514-appb-000037
计算公式：①组合(A+B)＝(B+Ba)：Y＝(4.901-63.00)/{1+(X/0.03216)^1.385}+63.00；②单用C：Y＝(-2.944-86.77)/{1+(X/1.182)^0.8216}+86.77。各栏目数值计算说明：(23)栏：将(1)栏数据用公式①算出；(24)栏：将(23)栏用公式②算出；(25)栏：(2)栏+(12)栏；(26)栏：将(25)栏数据用公式②算出。
综合(A+B)+C的等效剂量序贯兑换后预期相加效应值，即将表11～表16进行总结如下，见表17。
表17(A+B)+C组合的等效剂量序贯兑换后预期相加效应值。
Figure PCTCN2016097514-appb-000038
Figure PCTCN2016097514-appb-000039
(二)(A+C)+B的等效剂量序贯兑换
步骤与“(一)(A+B)+C的等效剂量序贯兑换”的步骤相同，简述如下：
第一步，以A为目标药物，将C进行等效剂量兑换后(AC)，合并等效剂量(A+AC)，用单用A的量效曲线方程，计算预期相加效应值。
第二步，以C为目标药物，将A进行等效剂量兑换后(Ca)，合并等效剂量(C+Ca)，用单用C的量效曲线方程，计算预期相加效应值。
第三步，以(A+C)＝(A+Ac)为目标药物，将B进行等效剂量兑换(Ab)，合并等效剂量[(A+Ac)+Ab]，用单用A量效曲线方程，计算预期相加效应值。
第四步，以(A+C)＝(C+Ca)为目标药物，将B进行等效剂量兑换(Cb)，合并等效剂量[(C+Ca)+Cb]，用单用C量效曲线方程，计算预期相加效应值。
第五步，以B为目标药物，将(A+C)＝(A+Ac)进行等效剂量兑换(B(A+Ac))，合并等效剂量[B+B(A+Ac)]，用单用B量效曲线方程，计算预期相加效应值。
第六步，以B为目标药物，将(A+C)＝(C+Ca)进行等效剂量兑换(B(C+Ca))，合并等效剂量[B+B(C+Ca)]，用单用B量效曲线方程，计算预期相加效应值。
每一步详细的计算步骤，均与“(A+B)+C的等效剂量序贯兑换”的计算相同，此处限于篇幅不列出，综合(A+C)+B的等效剂量序贯兑换后预期相加效应值，进行总结如下表18。
表18(A+C)+B组合的等效剂量序贯兑换后预期相加效应值。
Figure PCTCN2016097514-appb-000040
(三)(B+C)+A的等效剂量序贯兑换
步骤与“(一)(A+B)+C的等效剂量序贯兑换”的步骤相同，简述如下：
第一步，以B为目标药物，将C进行等效剂量兑换后(BC)，合并等效剂量(B+BC)，用单用B的量效曲线方程，计算预期相加效应值。
第二步，以C为目标药物，将B进行等效剂量兑换后(Cb)，合并等效剂量(C+Cb)，用单用C的量效曲线方程，计算预期相加效应值。
第三步，以(B+C)＝(B+Bc)为目标药物，将A进行等效剂量兑换(Ba)，合并等效剂量[(B+Bc)+Ba]，用单用B量效曲线方程，计算预期相加效应值。
第四步，以(B+C)＝(C+Cb)为目标药物，将A进行等效剂量兑换(Ca)，合并等效剂量[(C+Cb)+Ca]，用单用C量效曲线方程，计算预期相加效应值。
第五步，以A为目标药物，将(B+C)＝(B+Bc)进行等效剂量兑换(A(B+Bc))，合并等效剂量[A+A(B+Bc)]，用单用A量效曲线方程，计算预期相加效应值。
第六步，以A为目标药物，将(B+C)＝(C+Cb)进行等效剂量兑换(A(C+Cb))，合并等效剂量[A+A(C+Cb)]，用单用A量效曲线方程，计算预期相加效应值。
每一步详细的计算步骤，均与“(A+B)+C的等效剂量序贯兑换”的计算相同，此处限于篇幅不列出，综合(B+C)+A的等效剂量序贯兑换后预期相加效应值，进行总结如下表19。
表19(B+C)+A组合的等效剂量序贯兑换后预期相加效应值。
Figure PCTCN2016097514-appb-000041
步骤3重构量效曲线和拟合曲线方程
以合用组的依托泊苷(A)各剂量水平为横坐标，以三个(A+B)+C、(A+C)+B、(B+C)+A组合的预期相加效应值的数据为纵坐标，作出12条量效曲线(其中3条是同样的，因此图中所示为9条)。以最外侧的曲线作为围成量效曲带的边界，如图9A所示。
从图9A中可以看出，构成等效量效曲带的最外围的曲线为(A+Ab+Ac)和(C+Ca+Cb)，结合实际效应曲线与等效量效曲带的位置关系，认为这两条曲线围成的图像可以基本包含其它等效量效曲线。因此，可以此两条曲线重新作图，如图9B所示。
将合用组中依托泊苷(A)的浓度与预期相加效应等效线中(A+Ab+Ac)和(C+Ca+Cb)构成的外围效应值点的数值，进行新的构建量效方程拟合，得到围成预期相加效应量效曲带的两条曲线方程，分别为：
Y(A+B+C)：Y(A+Ab+Ac)＝(5.34-87.31)/{1+(X/0.2835)^0.7528}+87.31
Y(A+B+C)：Y(C+Ca+Cb)＝(6.376-86.2)/{1+(X/0.1374)^0.7008}+86.2
步骤4比较合用组预期相加效应量效曲带和实际量效曲线的位置关系，计算相关指标。
[1]目测结果：从图9B可以看出，合用剂量点的大多数位于相加效应量效曲带的上方，属于协同；实际效应曲线的上端一小部分区段与量效曲带相交，属于相加和拮抗的剂量范围。
[2]计算协同、相加和拮抗的剂量范围
从图9A和图9B中可以看出，实际效应量效曲线与量效曲带的两条曲线有明显交点，因此，需求解两个方程组。
方程组1
Y(A+B+C)：Y(A+Ab+Ac)＝(5.34-87.31)/{1+(X/0.2835)^0.7528}+87.31
三药合用中A：Y＝(17.01-84.13)/{1+(X/0.1083)^0.6546}+84.13
方程组2：
Y(A+B+C)：Y(C+Ca+Cb)＝(6.376-86.2)/{1+(X/0.1374)^0.7008}+86.2
三药合用中A：Y＝(17.01-84.13)/{1+(X/0.1083)^0.6546}+84.13
解方程组1，得出：X＝5.4883，Y＝79.3564。
解方程组2，得出：X＝1.8282Y＝75.0104
得出相加效应的依托泊苷(A)剂量界限是1.8282～5.4883μg/ml，根据A:B:C＝12.5:2:45的组合关系，很容易得到A+B+C相加效应的剂量范围为
依托泊苷(A)：1.8282～5.4883μg/ml；
长春新碱(B)：0.2925～0.8781μg/ml；
5-氟尿嘧啶(C)：6.5815～19.7579μg/ml。
依托泊苷(A)、长春新碱(B)和5-氟尿嘧啶(C)合用(A+B+C)，在固定比例A:B:C＝12.5:2:45(μg/ml+μg/ml+μg/ml)的三药合用，在共同的效应范围内，
协同效应剂量范围(A+B+C)：
[0.00004768+0.00000763+0.00017166，1.8282+0.2925+6.5815)μg/ml+ng/ml；
相加效应剂量范围(A+B+C)：
[1.8282+0.2925+6.5815，5.4883+0.8781+19.7579]μg/ml+ng/ml；
拮抗效应剂量范围(A+B+C)：
(5.4883+0.8781+19.7579，12.5+2+45]μg/ml+ng/ml
合用组实际效应量效曲线中属于相加效应的范围是：75.0104％～79.3564％
[3]计算CId和CIe(略)
第二部分其它几种三药合用组合协同、相加和拮抗的定量计算，包括：
1)依托泊苷(A)、长春新碱(B)和阿霉素(D)合用，固定比例A:B:D＝12.5:2:4(μg/ml)；
2)依托泊苷(A)、5-氟尿嘧啶(C)和阿霉素(D)合用，固定比例A:C:D＝12.5:45:4(μg/ml)；
3)长春新碱(B)、5-氟尿嘧啶(C)、阿霉素(D)合用，固定比例B:C:D＝2:45:4(μg/ml)；
计算步骤同第一部分A+B+C合用的计算(计算过程略)，主要结果如下：
A:B:D合用组重构的预期相加效应的量效曲带和实际量效曲线，如图10。
A:C:D合用组重构的预期相加效应的量效曲带和实际量效曲线，如图11。
B:C:D合用组重构的预期相加效应的量效曲带和实际量效曲线，如图12。
从图10、图11和图12这三个图可以看出，A:B:D、A:C:D和B:C:D三种药物组合，在固定比例下合用，实际效应的量效曲线基本上均低于预期相加效应曲带，大都属于拮抗效应的范围。
综合评价：在现有配伍条件下，四药中任意三药合用，与阿霉素合用者均会产生拮抗效应，只有A+B+C合用，才会产生协同效应。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (24)

  1. 一种联用药药效的处理方法，其特征在于，所述处理方法包括：
    获取所述联用药的预期相加效应的量效曲带，所述量效曲带由多条等效量效曲线中最外围的两条围成，所述等效量效曲线是指以所述联用药中的某一目标组分药的剂量为横坐标，以所述联用药等效兑换为任意一组分药所获得的预期相加效应为纵坐标而建立的曲线；所述等效兑换按照所获取的所述联用药中各组分药的用药顺序进行等效兑换；
    获取所述联用药的实际效应值随所述联用药中的所述某一目标组分药的剂量变化形成的实际量效关系曲线；
    比较所述实际量效关系曲线与所述量效曲带的位置关系，以及
    当所述实际量效关系曲线位于所述量效曲带的上方时，将所述联用药的药效输出为协同；
    当所述实际量效关系曲线位于所述量效曲带的下方时，将所述联用药的药效输出为拮抗；
    当所述实际量效关系曲线位于所述量效曲带范围内时，将所述联用药的药效输出为相加。
  2. 根据权利要求1所述的处理方法，其特征在于，所述联用药包括第一组分药A和第二组分药B，在获取所述联用药的预期相加效应的量效曲带的步骤之前，所述处理方法还包括建立多条所述等效量效曲线的步骤；其中，建立多条所述等效量效曲线的步骤包括：
    获取所述第一组分药A的第一量效关系曲线Y＝f(x)；
    获取所述第二组分药B的第二量效关系曲线Y＝g(x)；
    查找或计算所述第一量效关系曲线Y＝f(x)上所述第一组分药A在联用剂量Am下的效应值f(Am)；
    查找或计算所述第二量效关系曲线Y＝g(x)上与所述效应值f(Am)相同的所述第二组份药B的效应值g(Bm)所对应的等效剂量值Bm；
    计算所述第二组分药B的联用剂量Bn与所述等效剂量Bm的剂量和(Bn+Bm)；
    查找或计算所述第二量效关系曲线Y＝g(x)上所述第二组分药B的剂量为所述剂量和(Bn+Bm)时所对应的效应值g(Bn+Bm)；
    将所述效应值g(Bn+Bm)转换为所述联用药的预期相加效应值Y(Am+Bn)；
    建立所述联用药的预期相加效应值随所述第一组分药A的剂量变化的第一等效量效曲线Y(Am+Bn)＝g(Bn+Bm)；
    查找或计算所述第二量效关系曲线Y＝g(x)上所述第二组分药B在联用剂量Bn下的效应值g(Bn)；
    查找或计算所述第一量效关系曲线Y＝f(x)上与所述效应值g(Bn)相同的所述第一组分药A的效应值f(An)所对应的等效剂量值An；
    计算所述第一组分药A的联用剂量Am与所述等效剂量An的剂量和(Am+An)；
    查找或计算所述第一量效关系曲线Y＝f(x)上所述第一组分药A的剂量为所述剂量和(Am+An)时所对应的效应值f(Am+An)；
    将所述效应值f(Am+An)转换为所述联用药的预期相加效应值Y(Am+Bn)；
    建立所述联用药的预期相加效应值随所述第一组分药A的剂量变化的第二等效量效曲线Y(Am+Bn)＝f(Am+An)。
  3. 根据权利要求1或2所述的处理方法，其特征在于，当所述联用药的药效输出结果为协同时，在将所述联用药的药效输出为协同的步骤后，所述处理方法还包括：
    计算所述实际量效关系曲线位于所述量效曲带的上方时所对应的所述某一目标组分药的第一剂量范围；以及
    将所述第一剂量范围输出为所述某一目标组分药的协同剂量范围。
  4. 根据权利要求3所述的处理方法，其特征在于，在输出所述某一目标组分药的协同剂量范围后，所述处理方法还包括：
    获取所述联用药中所述某一目标组分药与其余组分药之间的联用关系；
    根据所述联用关系计算所述联用药中其余组分药在联用条件下的协同剂量范围；以及
    输出所述其余组分药的协同剂量范围。
  5. 根据权利要求1或2所述的处理方法，其特征在于，当所述联用药的药效输出结果为拮抗时，在将所述联用药的药效输出为拮抗的步骤后，所述处理方法还包括：
    计算所述实际量效关系曲线位于所述量效曲带的下方时所对应的所述某一目标组分药的第二剂量范围，以及
    将所述第二剂量范围输出为所述某一目标组分药的拮抗剂量范围。
  6. 根据权利要求5所述的处理方法，其特征在于，在输出所述某一目标组分药的拮抗剂量范围后，所述处理方法还包括：
    获取所述联用药中所述某一目标组分药与其余组分药之间的联用关系；
    根据所述联用关系计算所述联用药中其余组分药在联用条件下的拮抗剂量范围；以及
    输出所述其余组分药的拮抗剂量范围。
  7. 根据权利要求1或2所述的处理方法，其特征在于，当所述联用药的药效输出结果为相加时，在将所述联用药的药效输出为相加的步骤后，所述处理方法还包括：
    计算所述实际量效关系曲线位于所述量效曲带范围内时所对应的所述某一目标组分药的第三剂量范围；以及
    将所述第三剂量范围输出为所述某一目标组分药的相加剂量范围。
  8. 根据权利要求7所述的处理方法，其特征在于，在输出所述某一目标组分药的相加剂量范围后，所述处理方法还包括：
    获取所述联用药中所述某一目标组分药与其余组分药之间的联用关系；
    根据所述联用关系计算所述联用药中其余组分药在联用条件下的相加剂量范围；以及
    输出所述其余组分药的相加剂量范围。
  9. 根据权利要求1或2所述的处理方法，其特征在于，比较所述实际量效关系曲线与所述量效曲带的位置关系的步骤包括：
    获取所述某一目标组分药在特定联用剂量下，对应的所述联用药在所述量效曲带范围内的预期相加效应的最小值和最大值；
    获取所述某一目标组分药在所述特定联用剂量下，对应的所述联用药在所述实际量效关系曲线上的实际效应值；
    计算所述实际效应值与所述预期相加效应的最小值的第一比值；
    计算所述实际效应值与所述预期相加效应的最大值的第二比值；
    将所述第一比值和所述第二比值分别标记为CId1和CId2；
    若所述CId1和CId2均大于1，则确定所述实际量效关系曲线位于所述量效曲带的上方；
    若所述CId1和CId2均小于1，则确定所述实际量效关系曲线位于所述量效曲带的下方；
    若所述CId1和CId2中任一个≧1或≦1，则确定所述实际量效关系曲线位于所述量效曲带的范围内。
  10. 根据权利要求9所述的处理方法，其特征在于，在将所述第一比值和所述第二比值分别标记为CId1和CId2的步骤后，所述处理方法还包括输出所述CId1和CId2的步骤。
  11. 根据权利要求1或2所述的处理方法，其特征在于，比较所述实际量效关系曲线与所述量效曲带的位置关系的步骤包括：
    获取所述联用药在所述量效曲带上产生特定效应时所对应的所述某一目标组分药的剂量的最小值和最大值；
    获取所述联用药在所述实际量效关系曲线上产生所述特定效应时所需要的实际联用剂量；
    计算所述实际联用剂量与所述最小值的第三比值；
    计算所述实际联用剂量与所述最大值的第四比值；
    将所述第三比值和所述第四比值分别标记为CIe1和CIe2；
    若所述CIe1和CIe2均小于1，则确定所述实际量效关系曲线位于所述量效曲带的上方；
    若所述CIe1和CIe2均大于1，则确定所述实际量效关系曲线位于所述量效曲带的下方；
    若所述CIe1和CIe2中任一个≧1或≦1，则确定所述实际量效关系曲线位于所述量效曲带的范围内。
  12. 根据权利要求11所述的处理方法，其特征在于，在将所述第三比值和所述第四比值分别标记为CIe1和CIe2的步骤后，所述处理方法还包括输出所述CIe1和CIe2的步骤。
  13. 一种联用药药效的处理装置，其特征在于，所述处理装置包括：
    第一获取模块，用于获取所述联用药的预期相加效应的量效曲带，所述量效曲带由多条等效量效曲线中最外围的两条围成，每条所述等效量效曲线是指以所述联用药中的某一目标组分药的剂量为横坐标，以所述联用药等效兑换为任意一组分药所获得的预期相加效应为纵坐标而建立的曲线；所述等效兑换按照所述联用药中各组分药的用药顺序进行等效兑换；
    第二获取模块，用于获取所述联用药的实际效应值随所述联用药中的所述某一目标组分药的剂量变化形成的实际量效关系曲线；
    第一比较模块，用于比较所述实际量效关系曲线与所述量效曲带的位置关系，以及第一输出模块，用于当所述实际量效关系曲线位于所述量效曲带的上方时，将所述联用药的药效输出为协同；
    第二输出模块，用于当所述实际量效关系曲线位于所述量效曲带的下方时，将所述联用药的药效输出为拮抗；
    第三输出模块，用于当所述实际量效关系曲线位于所述量效曲带范围内时，将所述联用药的药效输出为相加。
  14. 根据权利要求13所述的处理装置，其特征在于，所述联用药包含第一组分药A和第二组分药B，所述处理装置还包括等效量效曲线建立模块，所述等效量效曲线建立模块用于在所述第一获取模块获取所述联用药的预期相加效应的量效曲带的步骤之前建立多条所述等效量效曲线；所述等效量效曲线建立模块包括：
    第一获取单元，用于获取所述第一组分药A的第一量效关系曲线Y＝f(x)；
    第二获取单元，用于获取所述第二组分药B的第二量效关系曲线Y＝g(x)；
    第一查找单元，用于查找或计算所述第一量效关系曲线Y＝f(x)上所述第一组分药A在联用剂量Am下的效应值f(Am)；
    第二查找单元，用于查找或计算所述第二量效关系曲线Y＝g(x)上与所述效应值f(Am)相同的所述第二组份药B的效应值g(Bm)所对应的等效剂量值Bm；
    第一计算单元，用于计算所述第二组分药B的联用剂量Bn与所述等效剂量Bm的剂量和Bm+Bn；
    第三查找单元，用于查找或计算所述第二量效关系曲线Y＝g(x)上所述第二组分药B的剂量为所述剂量和时所对应的效应值g(Bn+Bm)；
    第一转换单元，用于将所述效应值g(Bn+Bm)转换为所述联用药的预期相加效应值Y(Am+Bn)；以及
    第一曲线建立单元，用于建立所述联用药的预期相加效应随所述第一组分药A的剂量变化的第一等效量效曲线Y(Am+Bn)＝g(Bn+Bm)；
    第四查找单元，用于查找或计算所述第二量效关系曲线Y＝g(x)上所述第二组分药B在联用剂量Bn下的效应值g(Bn)；
    第五查找单元，用于查找或计算所述第一量效关系曲线Y＝f(x)上与所述效应值g(Bn)相同的所述第一组分药A的效应值f(An)所对应的等效剂量值An；
    第二计算单元，用于计算所述第一组分药A的联用剂量Am与所述等效剂量An的剂量和(Am+An)；
    第六查找单元，用于查找或计算所述第一量效关系曲线Y＝f(x)上所述第一组分药A的剂量为所述剂量和(Am+An)时所对应的效应值f(Am+An)；
    第二转换单元，用于将所述效应值f(Am+An)转换为所述联用药的预期相加效应值Y(Am+Bn)；
    第二曲线建立单元，用于建立所述联用药的预期相加效应值随所述第一组分药A的剂量变化的第二等效量效曲线Y(Am+Bn)＝f(Am+An)。
  15. 根据权利要求13或14所述的处理装置，其特征在于，所述处理装置还包括：
    第一计算模块，用于在所述第一输出模块将所述联用药的药效输出为协同后，计算所述实际量效关系曲线位于所述量效曲带的上方时所对应的所述某一目标组分药的第一剂量范围；以及
    第四输出模块，用于将所述第一剂量范围输出为所述某一目标组分药的协同剂量范围。
  16. 根据权利要求15所述的处理装置，其特征在于，所述处理装置还包括：
    第三获取模块，用于在所述第四输出模块将所述第一剂量范围输出为所述某一目标组分药的协同剂量范围之后，获取所述联用药中所述某一目标组分药与其余组分药之间的联用关系；
    第二计算模块，用于根据所述联用关系计算所述联用药中其余组分药在联用条件下的协同剂量范围；以及
    第五输出模块，用于输出所述其余组分药的协同剂量范围。
  17. 根据权利要求13或14所述的处理装置，其特征在于，所述处理装置还包括：
    第三计算模块，用于在所述第二输出模块后将所述联用药的药效输出为拮抗后，计算所述实际量效关系曲线位于所述量效曲带的下方时所对应的所述某一目标组分药的第二剂量范围，以及
    第六输出模块，用于将所述第二剂量范围输出为所述某一目标组分药的拮抗剂量范围。
  18. 根据权利要求17所述的处理装置，其特征在于，所述处理装置还包括：
    第四获取模块，用于在所述第六输出模块将所述第二剂量范围输出为所述某一目标组分药的拮抗剂量范围后，获取所述联用药中所述某一目标组分药与其余组分药之间的联用关系；
    第四计算模块，用于根据所述联用关系计算所述联用药中其余组分药在联用条件下的拮抗剂量范围；以及
    第七输出模块，用于输出所述其余组分药的拮抗剂量范围。
  19. 根据权利要求13或14所述的处理装置，其特征在于，所述处理装置还包括：
    第五计算模块，用于在所述第三输出模块将所述联用药的药效输出为相加后，计算所述实际量效关系曲线位于所述量效曲带范围内时所对应的所述某一目标组分药的第三剂量范围；以及
    第八输出模块，用于将所述第三剂量范围输出为所述某一目标组分药的相加剂量范围。
  20. 根据权利要求19所述的处理装置，其特征在于，所述处理装置还包括：
    第五获取模块，用于在所述第八输出模块将所述第三剂量范围输出为所述某一目标组分药的相加剂量范围后，获取所述联用药中所述某一目标组分药与其余组分药之间的联用关系；
    第六计算模块，用于根据所述联用关系计算所述联用药中其余组分药在联用条件下 的相加剂量范围；以及
    第九输出模块，用于输出所述其余组分药的相加剂量范围。
  21. 根据权利要求13或14所述的处理装置，其特征在于，第一比较模块包括：
    第一获取子模块，用于获取所述某一目标组分药在特定联用剂量下，对应的所述联用药在所述量效曲带范围内的预期相加效应的最小值和最大值；
    第二获取子模块，用于获取所述某一目标组分药在所述特定联用剂量下，对应的所述联用药在所述实际量效关系曲线上的实际效应值；
    第一计算子模块，用于计算所述实际效应值与所述预期相加效应的最小值的第一比值；
    第二计算子模块，用于计算所述实际效应值与所述预期相加效应的最大值的第二比值；
    第一标记子模块，用于将所述第一比值和所述第二比值分别标记为CId1和CId2；
    第一确定子模块，用于当所述CId1和CId2均大于1时，确定所述实际量效关系曲线位于所述量效曲带的上方；
    第二确定子模块，用于当所述CId1和CId2均小于1，确定所述实际量效关系曲线位于所述量效曲带的下方；以及
    第三确定子模块，用于当所述CId1和CId2中任一个≧1或≦1，确定所述实际量效关系曲线位于所述量效曲带的范围内。
  22. 根据权利要求21所述的处理装置，其特征在于，所述处理装置还包括第十一输出模块，用于在所述第一标记子模块将所述第一比值和所述第二比值分别标记为CId1和CId2之后，输出所述CId1和CId2。
  23. 根据权利要求13或14所述的处理装置，其特征在于，第一比较模块包括：
    第三获取子模块，用于获取所述联用药在所述量效曲带上产生特定效应时所对应的所述某一目标组分药的剂量的最小值和最大值；
    第四获取子模块，用于获取所述联用药在所述实际量效关系曲线上产生所述特定效应时所需要的实际联用剂量；
    第三计算子模块，用于计算所述实际联用剂量与所述最小值的第三比值；
    第四计算子模块，用于计算所述实际联用剂量与所述最大值的第四比值；
    第二标记子模块，用于将所述第三比值和所述第四比值分别标记为CIe1和CIe2；
    第四确定子模块，用于当所述CIe1和CIe2均小于1时，确定所述实际量效关系曲线 位于所述量效曲带的上方；
    第五确定子模块，用于当所述CId1和CId2均大于1时，确定所述实际量效关系曲线位于所述量效曲带的下方；以及
    第六确定子模块，用于当所述CId1和CId2中任一个≧1或≦1时，确定所述实际量效关系曲线位于所述量效曲带的范围内。
  24. 根据权利要求23所述的处理装置，其特征在于，所述处理装置还包括第十二输出模块，用于在所述第二标记子模块将所述第三比值和所述第四比值分别标记为CIe1和CIe2后，输出所述CId1和CId2。
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