年1月23日 CalcuSyn is a software tool whose main purpose is to aid individuals in analyzing mixed drug treatments, a more and more used practice in. combination-index data generated by CalcuSyn software analyses .. and antagonism, respectively (Source: CalcuSyn manual, Biosoft, ). Manual and Software, Biosoft, Cambridge, U.K., Chou, T.-C. and Hayball , M. CalcuSyn for Windows, Multiple-drug dose-effect analyzer and manual.

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Production of other copies is not permitted. Storage of this program in any other computer format or retrieval system or transmittal in any form without prior permission of the publisher is strictly forbidden. Prined in the U.

Run the installation program, called setup. Note that the CD version has Autorun and, if your computer is suitable, that will present a menu on-screen from which you can select the Install option. Registration The first time you run CalcuSyn, you will be presented with a falcusyn containing a serial number and requesting a password. The serial number generated by the program.

Once you have entered the correct password, you will be able to run CalcuSyn repeatedly. Note that until you have entered the correct password, you will not be able to run CalcuSyn at all. You can get this from the Help About menu option. Your order reference code or license number. The version of Windows you are using. The exact text of any error or warning messages produced by CalcuSyn or Windows when the problem occurred. Whether or not you have been able to replicate the problem and, if so, the steps necessary valcusyn do so.

The mass-action law is the basic law in Nature that forms the basis for the chemical equilibrium dynamics, physical absorption isotherm of Langmuir, biological receptor theory and enzyme kinetics. It is a rigorous and well developed discipline.

Unlike empirical or statistical approaches in doseeffect analysis in biology, the mass-action law provides well defined models for mathematical derivations. A Derived Unified Theory: By using the enzyme kinetic models of the mass-action law, Chou derived and reported several hundred equations for different numbers of substrates, products, reaction sequences, and different types of inhibitions There are ten review articles that have been published, including three in encyclopedias 11,13, CalcuSyn 10 The Median-Effect Principle The Median-effect Equation of Chou A general equation for dose-effect relationship was derived by Chou 1,2 through mathematical induction using hundreds of enzyme kinetic models.

It is determined from the x-intercept of the median-effect plot. It is determined by the slope of the medianeffect plot. Thus, Dm and m parameters representing the potency and shape, respectively, determine the entire dose-effect curve.

The Dm can also be determined by: The goodness of fit for the data to the median-effect equation is represented by the linear correlation coefficient r of the median-effect plot. An equation determines only the additive effect rather than synergism or antagonism.

However, we define synergism as a more than expected additive effect, and antagonism as a less than expected additive effect.

Dx 1 and Dx 2 in the denominators of Eq. Dx can be readily calculated from Eq. For simplicity, mutual exclusivity is usually assumed when more than two drugs are involved in combinations 8,9, One can generate isobolograms at different effect levels, e. However, if too many effect levels are selected, the isobolograms frequently become messy and difficult to read. The general isobologram equation for the n drug combination has been derived by Chou and Talalay 8,9.

The Dose-reduction Index of Chou The dose-reduction index DRI is a measure of how much the dose of each drug in a synergistic combination may be reduced at a given effect level compared with the doses for each drug alone. This terminology was formerly introduced by J. Chou in 12and has since been used in many publications For two drug combinations, we may define from Eq.

Complexity and Pitfalls There are ambiguous definitions of synergism and numerous unsubstantiated claims of synergy in biomedical literature. For example, in one review alone Goldin, A. Even in recent years, empirical and arbitrary methods for drug combination analysis have been used despite the fact that they are merely descriptive and either lack formal derivation of their equations or completely lack equations for quantitative analysis.

These ambiguous practices generate confusion. The pitfalls of synergy interpretation are described in Ref. Experimental Design for Drug-combination Studies There are several basic requirements in experimental design for determination of synergism or antagonism: Prerequisite Dose-effect Curves Each drug alone should have a dose-effect relationship.

Both potency Dm and shape m parameters are essential for determining synergism or antagonism. Instead, potentiation augmentation, enhancement or inhibition suppression can be determined. Prerequisite Number of Data Points At least three or more data points for each single drug are required for the determination of potency and shape and thus for the determination of CI values.

For combinations, in contrast, any number of data points can be used for the CI calculations. Accuracy of Measurement and Conformity to the Mass-action Law The linear correlation coefficient, r, of the median-effect plot should be reasonably good. The following r values are usually obtained: Constant Ratio Combination Design The most efficient way for experimental design is to choose the combination drugs at their equipotent ratio e.

Sometimes, more than one ratio is made e. Checker board or Latin-square design. CalcuSyn 14 The advantages of the constant ratio design are: Each mixture can be treated as a drug to obtain Dm and m parameters, and for the automated construction of Fa-CI table, Fa-CI plot and classic and conservative isobolograms.

As indicated by the multiple drug-effect equation of Chou-Talalay 6, 8each term of the equation is the dividing ratio and, therefore, the unit for each term single drug term or drug combination term cancels out and becomes a dimensionless quantity. Therefore, two drugs with different units e. M, mM or IU can be combined and the results analyzed as usual. For the Dm 1,2, the ratio for D1 and D2 can resolve the differences in units.

Non-constant Ratio Combination Design Sometimes, researchers design their drug combinations with random or arbitrary ratios, or vary the concentrations of one drug while keeping the second drug concentration fixed. As long as the m and Dm parameters for each single drug are available, the CI values for each data point of the nonconstant ratio design can still be calculated.

However, this design will not provide Fa-CI plot simulation although the combination data points can be placed on the Fa-CI plot. Furthermore, the classic isobologram or the conservative isobologam cannot be constructed for the non-constant ratio design.

However, the Dx-normalized isobologam can be constructed automatically. This normalize isobologram provides information of synergism or antagonism of each combination data point but will not provide the information of the dose and Fa in the normalized isobologram. Combination of more than Two Drugs For three drug combinations e.

Two drug combinations, if used, should be correspond to three drug ratios so that D1: In this case, the component combinations can also be manula for their synergism or antagonism e. For the combination of more than three drugs 8,14 the same principles and rules apply. Application of the Chou-Talalay Method 15 Application of the Chou-Talalay Method Scope of Application Since both the median-effect equation of Chou and the combination-index equation of Chou-Talalay are general equations derived from the massaction law models, their derivations have rigorous mathematical proof and systematic documentation.

The simplicity of the general equations makes for versatility in their applications. The method has been applied to various scientific disciplines.

### Biosoft: Software for Science

Some of the early applications have been described in the review articles given in Ref. This design can be expanded to a large dose range or larger density. It can also be extended to multiple ratios e. The errors of estimate can be from several caclusyn, e. The r value of the median-effect plot provides a first line of statistics.

There calcusun no easy way to answer the synergy question. Several relevant points need to be considered: Accuracy of measurement and biological variability. Synergism at what dose level? Whether synergy is treatment schedule dependent or combination ratio dependent?

The following table shows the recommended symbols and descriptions for presenting the degrees manua synergism or antagonism. The ranges of CI and the symbols are refined from those described earlier by Chou If any CI value s are greater than 2, it is recommended that the antilog of the averaged log CI value is used to avoid significant biases of overestimating antagonism.

## Computer Software

Callcusyn and Isobol Equations for n Drugs. For mutually exclusive drugs, the combination index equation for the combination of n inhibitors 6, 8, 14 can be described by: The n can manul partitioned into any combination of two parts which can be assigned to the two coordinates of the isobol 8.

Using the Program 19 CalcuSyn: The left-hand pane will be populated with the experiment basics. Double-click on Experiment Details to enter the experiment properties.

### Download CalcuSyn

Double-click on Raw Data to open the raw data grid to enter calcusgn data. You can save an experiment using the File Save option and open an existing experiment calcuusyn the File Open command.

Using the Contents Pane On the left-hand side of the program screen is the contents pane that shows the contents of your experiment see below. Double click on items in the pane to open them. The following examples are based around the sample1. This and the other sample files, called sample2. This will open the first page of the wizard.