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Tingchao Chou - One of the best experts on this subject based on the ideXlab platform.
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Abstract 5510: Mass-Action Law based general pharmacodynamics theory and algorithm for quantitative computer simulation of drug-evaluations in cells, in animals and in clinical trials
Clinical Research (Excluding Clinical Trials), 2020Co-Authors: Tingchao ChouAbstract:The Median-Effect Equation (MEE) for single drug, and the Combination Index Equation (CIE) for multiple drug combinations, are basis for general Pharmacodynamics (PD), and Biodynamics (BD). Both, MEE and CIE are derived from system analysis of the Mass-Action Law (MAL). The MAL-PD/BD theory, equations and algorithms allow automated computer simulations for diagnostic plots and quantitative, digital/indexed conclusions. To date, the MAL dynamic theory is cited over 15,000 times, in over 1,248 biomedical journals. The publications include studies in vitro, in cell, in animal and in clinical trial levels, as indicated in Google Scholar Citations -Ting-Chao Chou, or in Pharmacol. Rev. 58: 621-681, 2006 (cited 3,119 times in 914 journals). MEE indicates dose and effect are interchangeable, and all PD Dose-Effect curves (DEC) can be linearized by the Median-Effect Plot (MEP), x= Log (dose) vs y= Log {(frAction affected (fa)/(frAction unaffected (fu)}, where fa+fu=1, and when fa=fu, gives the Median-Effect Dose (Dm). The slope gives “m” value (dynamic order, signifying the shape of DEC), and the Antilog of x-intercept gives the “Dm” value, (signifying the potency of half-affected, such as IC50, ED50, or LD50). The MEE, is the unified theory of the Michaelis-Menten Eq. for enzyme half-saturation, Handerson-Hasselbalch Eq. for pH half-ionization, Hill Eq. for ligand half-occupancy, and the Scatchard Eq, for receptor half-bond and half-free. Since MEP linearizes the DEC, it requires only a minimum of two data pints to simulate entire DEC. Thus, the Two-Data-Point Theory is extremely cost-effective for animal studies and clinical trial protocol designs, as only small number data points is required to achieve efficient computer simulations, with digital/index conclusions. In CIE, CI 1, quantitatively defines Synergism, Additive Effect, and Antagonism, respectively, for 2 to n drug combs, using CompuSyn. PD requires multiple doses (3-4 doses in animals; 2-3 doses in clinical trials) since single dose yields a data Point, but “a point” which has “no shape”, thus, it is Not a PD in Vivo. For 2-drug-combos using the CI method in vivo for drug A, B, and A+B, require only 10 data points, (3+3+3 plus one control). Earlier examples with CI method in vivo are: 1. Anti-HIV Combos (AZT+IFN, using only 36 AIDS patients), and 2. Anti-cancer Combos (Taxotere+T607, against HCT-116 colon carcinoma xenograft in nude mice), both used only 10 data points and both achieved quantitative determination of Synergism. This report reaffirm Example 2 with the same drug combos against MX-1 mammary carcinoma xenograft in nude mice, using only 10 data points, showed similar synergy at ED75 to ED97, CI= 0.82-0.79 for MX-1, and CI= 0.98-0.64 for HCT-116. Citation Format: Ting-Chao Chou. Mass-Action Law based general pharmacodynamics theory and algorithm for quantitative computer simulation of drug-evaluations in cells, in animals and in clinical trials [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5510.
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Drug combination in vivo using combination index method: Taxotere and T607 against colon carcinoma HCT-116 xenograft tumor in nude mice
Synergy, 2016Co-Authors: Ning Zhang, Joseph H. Chou, Hua-jin Dong, Shu-fu Lin, Gudrun Ulrich-merzenich, Tingchao ChouAbstract:Abstract The median-effect equation (MEE) of the Mass-Action Law and the combination index (CI) theorem have been used for quantitative determination of synergism (CI 1) and additive effect (CI = 1) in animals in vivo . Experimental design, the theoretical algorithm and the CompuSyn software simulation have been used to illustrate step-by-step for the combination of two anti-cancer agents, Taxotere and T607 compound, with similar mode of Actions of targeting microtubule polymerization, but with distinct chemical structures. These two compounds acted synergistically against human colon carcinoma HCT-116 xenograft tumor in athymic nude mice. In all, only 78 nude mice have been used. The synergy is especially significant (p in vivo experimentations. Most significantly, the Mass-Action Law based algorithm provides quantitative indexed conclusions.
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Frequently asked questions in drug combinations and the Mass-Action Law-based answers
Synergy, 2014Co-Authors: Tingchao ChouAbstract:Summary Drug combinations have been widely used in the treatment of the most dreadful diseases, such as cancer and AIDS. In the search for synergistic combinations for therapy, numerous articles have been published during the past century. However, the term “synergy” has at least 20 different definitions in literature but none supports others. The confusion on synergy claims has far reaching consequences in biomedical research, drug discovery and development, regulation, and medical care of patients. This article reviews the current status and enlists the frequently occurred pit-falls, misconceptions and common errors in drug combination studies. The questions and issues are contemplated to be answered and clarified with the physico-chemical algorithms of the Mass-Action Law, specifically with the unified theory of the median-effect equation and its combination index theorem for drug combinations. The derived theory, algorithm and its computer simulation lead to a quantitative indexed bioinformatics, and econo-green bio-research using small number of data points.
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Abstract 5526: Mass-Action Law algorithm-based computer simulation for efficient and econo-green cancer drug discovery and development.
Experimental and Molecular Therapeutics, 2013Co-Authors: Tingchao ChouAbstract:Physico-chemical principle of the Mass-Action Law algorithm (MALA) is the basis for systematic pharmacodynamics (PD) that leads to general median-effect equation (MEE) for single entity effect and the combination index equation (CIE) for multiple entity interActions (Chou TC, Pharmacol. Rev. 58: 621-681, 2006; Free web access: http://pharmrev.aspetjournals.org/content/58/3/621). “Median” is the common-link and universal reference point for single and multiple entities and for 1st-order and higher-order dynamics. Median is also the harmonic mean of kinetic constants where the harmony is the state of pure non-competitiveness [Chou, Nature Precedings (npre.2008.2064-2). Available free at http://precedings.nature.com/documents/2064/version/2]. Based on MEE, all dose-effect curves whether hyperbolic or sigmoidal, weak or strong, 1st-order or higher-order, in vitro or in vivo, can be linearlized by the median-effect plot with small number of data points in small size experiments (Chou, J. Theor. Biol. 59: 253-276, 1976; Pharmacol. Rev. .ibid). Based on CIE, CI 1 quantitatively indicates synergism, additive effect, and antagonism, respectively (Chou & Talalay, Adv. Enz. Regul. 22: 27-55, 1984; Cancer Res. 70: 440-446, 2011). Thus. MEE is the common denominator for simple and complex bio-systems in vitro, in animal and in clinics. Computerized simulation of MEE or CIE can take Citation Format: Ting-Chao Chou. Mass-Action Law algorithm-based computer simulation for efficient and econo-green cancer drug discovery and development. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5526. doi:10.1158/1538-7445.AM2013-5526 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
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The Mass-Action Law based algorithm for cost-effective approach for cancer drug discovery and development.
American journal of cancer research, 2011Co-Authors: Tingchao ChouAbstract:The Mass-Action Law based system analysis via mathematical induction and deduction lead to the generalized theory and algorithm that allows computerized simulation of dose-effect dynamics with small size experiments using a small number of data points in vitro, in animals, and in humans. The median-effect equation of the Mass-Action Law deduced from over 300 mechanism specific-equations has been shown to be the unified theory that serves as the common-link for complicated biomedical systems. After using the median-effect principle as the common denominator, its applications are mechanism-independent, drug unit-independent, and dynamic order-independent; and can be used generally for single drug analysis or for multiple drug combinations in constant-ratio or non-constant ratios. Since the “median” is the common link and universal reference point in biological systems, these general enabling lead to computerized quantitative bio-informatics for econo-green bio-research in broad disciplines. Specific applications of the theory, especially relevant to drug discovery, drug combination, and clinical trials, have been cited or illustrated in terms of algorithms, experimental design and computerized simulation for data analysis. Lessons learned from cancer research during the past fifty years provide a valuable opportunity to reflect, and to improve the conventional divergent approach and to introduce a new convergent avenue, based on the Mass-Action Law principle, for the efficient cancer drug discovery and the low-cost drug development.
D. Browarzik - One of the best experts on this subject based on the ideXlab platform.
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liquid liquid equilibrium calculation in binary water nonionic surfactant ciej systems with a new Mass Action Law model based on continuous thermodynamics
Fluid Phase Equilibria, 2005Co-Authors: C. Browarzik, D. BrowarzikAbstract:Abstract A systematic study of the LLE for a number of aqueous solutions of n -alkyl polyglycol ethers (C i E j ) with tail length i from 4 to 12 and head length j from 1 to 6 is presented. For calculation a new thermodynamic model was developed basing on the Mass-Action Law and continuous thermodynamics. Besides the micellization the self association of water is taken into account. The resulting polydisperse mixture of micelles and water associates is described by two continuous aggregation-size distribution functions depending on temperature and surfactant concentration. The Gibbs energy of the mixture is calculated by the Flory-Huggins theory with a temparature dependent parameter χ . The model is applied to 13 water + C i E j systems with LCST behavior and to the three systems water + C 4 E 1 , water + C 10 E 4 and water + C 10 E 5 with closed-loop miscibility gaps. For the former 13 systems four parameters were fitted to the experimental equilibrium data. For the systems with closed-loop miscibility gaps two additional parameters were necessary, due two the more extended temperature range. The agreement between calculated and experimental data is very good for nearly all systems of both types.
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Liquid–liquid equilibrium calculation in binary water + nonionic surfactant CiEj systems with a new Mass-Action Law model based on continuous thermodynamics
Fluid Phase Equilibria, 2005Co-Authors: C. Browarzik, D. BrowarzikAbstract:Abstract A systematic study of the LLE for a number of aqueous solutions of n -alkyl polyglycol ethers (C i E j ) with tail length i from 4 to 12 and head length j from 1 to 6 is presented. For calculation a new thermodynamic model was developed basing on the Mass-Action Law and continuous thermodynamics. Besides the micellization the self association of water is taken into account. The resulting polydisperse mixture of micelles and water associates is described by two continuous aggregation-size distribution functions depending on temperature and surfactant concentration. The Gibbs energy of the mixture is calculated by the Flory-Huggins theory with a temparature dependent parameter χ . The model is applied to 13 water + C i E j systems with LCST behavior and to the three systems water + C 4 E 1 , water + C 10 E 4 and water + C 10 E 5 with closed-loop miscibility gaps. For the former 13 systems four parameters were fitted to the experimental equilibrium data. For the systems with closed-loop miscibility gaps two additional parameters were necessary, due two the more extended temperature range. The agreement between calculated and experimental data is very good for nearly all systems of both types.
Pascal André - One of the best experts on this subject based on the ideXlab platform.
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Plasma Concentrations out of Equilibrium: N2 (Kinetic Method and Mass Action Law), Ar-CCl4 and Ar-H2-CCl4 (Mass Action Law)
Annals of the New York Academy of Sciences, 1999Co-Authors: Pascal André, Jacques Aubreton, Marie-françoise Elchinger, Pierre Fauchais, André LefortAbstract:The multi-temperature Gibbs free energy minimization (GFEM) method has been compared to the Pseudo Kinetic Method (PKM) to calculate the composition of a nitrogen plasma at atmospheric pressure. When introducing only two temperatures Te and Th with their ratio e = 2, the GFEM method overestimates by more than two orders of magnitude the density of N2+. However when calculating the kinetic rate coefficient at different temperatures the thermodynamic relationship between them and the equilibrium constant is no more fulfilled. That is why an intermediate temperature T* between Te and Th has been introduced linked to the ratio of the electrons flux to that of neutrals and e has been assumed to vary with the electron density ne, equilibrium (e = 1) being achieved either for nemax = 1022 or 1023 m-3. With nemax = 1022 m-3 the agreement between the results obtained with the PKM and the GFEM method is fairly good. That is why this latter method has been used to calculate the composition of complex mixtures of Ar-CCl4 and Ar-H2-CCl4. Below 6000 K where complex molecules exist the variation of e between 2.5 and 1.5 does not affect very much the composition which, however, depends strongly on v (v = Tv/Th)
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Comparison between Gibbs Free Energy Minimization and Mass Action Law for a Multitemperature Plasma with Application to Nitrogen
Plasma Chemistry and Plasma Processing, 1997Co-Authors: Pascal André, M'hammed Abbaoui, Roger Bessege, André LefortAbstract:This paper gives all the necessary physical equations to determine the composition and the thermodynamic in a multitemperature plasma utilizing two different methods: the first method is based on Gibbs free energy minimization and the second is based on the resolution of the Mass Action Law. The lowering terms of the ionization potential and thermodynamic properties are given for multitemperature plasma using the Debye-Huckel approximation. Numerical application is made to a nitrogen plasma.
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COMPARISON BETWEEN GIBBS FREE ENERGY MINIMIZATION AND Mass Action Law FOR A MULTITEMPERATURE PLASMA WITH APPLICATION TO NITROGEN
Plasma Chemistry and Plasma Processing, 1997Co-Authors: Pascal André, M'hammed Abbaoui, Roger Bessege, André LefortAbstract:This paper gives all the necessary physical equations to determine the composition and the thermodynamic properties in a multitemperature plasma utilizing two different methods: the first method is based on Gibbs free energy minimization and the second is based on the resolution of the Mass Action Law. The lowering terms of the ionization potential and thermodynamic properties are given for a multitemperature plasma using the Debye-Huckel approximation. Numerical application is made to a nitrogen plasma.
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Numerical method and composition at and out of chemical equilibrium in a multitemperature plasma. Application to a pure nitrogen plasma
Contributions to Plasma Physics, 1997Co-Authors: Pascal AndréAbstract:The disequilibrium between the temperatures (excitation, rotation, vibration, translation) in plasmas lead us to specific chemical potentials. Then, they are used to develop a Mass Action Law in a multitemperature plasma. This Mass Action Law enables us to determine the composition of a pure nitrogen mixture out of thermal equilibrium. The composition evolution versus time is determined from a kinetic method modified to take into account different temperature hypotheses. The composition and different thermodynamic properties of a pure nitrogen mixture are given at the chemical equilibrium, then versus time for various temperature hypotheses and thermal disequilibriums.
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Numerical Method and Composition at and out of Chemical Equilibrium in a Multitemperature Plasma. Application to a Pure Nitrogen Plasma
Contributions to Plasma Physics, 1997Co-Authors: Pascal AndréAbstract:The disequilibrium between the temperatures (excitation, rotation, vibration, translation) in plas- mas lead us to specific chemical potentials. Then, they are used to develop a Mass Action Law in a multitemperaturc plasma. This Mass Action Law enables us to determine the composition of a pure nitrogen mixture out of thermal equilibrium. The composition evolution versus time is determined from a kinetic method modified to take into account different temperature hypotheses. The composition and different thermodynamic properties of a pure nitrogen mixture are given at the chemical equilibrium, then versus time for various temperature hypotheses and thermal disequi- libriums.
C. Browarzik - One of the best experts on this subject based on the ideXlab platform.
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liquid liquid equilibrium calculation in binary water nonionic surfactant ciej systems with a new Mass Action Law model based on continuous thermodynamics
Fluid Phase Equilibria, 2005Co-Authors: C. Browarzik, D. BrowarzikAbstract:Abstract A systematic study of the LLE for a number of aqueous solutions of n -alkyl polyglycol ethers (C i E j ) with tail length i from 4 to 12 and head length j from 1 to 6 is presented. For calculation a new thermodynamic model was developed basing on the Mass-Action Law and continuous thermodynamics. Besides the micellization the self association of water is taken into account. The resulting polydisperse mixture of micelles and water associates is described by two continuous aggregation-size distribution functions depending on temperature and surfactant concentration. The Gibbs energy of the mixture is calculated by the Flory-Huggins theory with a temparature dependent parameter χ . The model is applied to 13 water + C i E j systems with LCST behavior and to the three systems water + C 4 E 1 , water + C 10 E 4 and water + C 10 E 5 with closed-loop miscibility gaps. For the former 13 systems four parameters were fitted to the experimental equilibrium data. For the systems with closed-loop miscibility gaps two additional parameters were necessary, due two the more extended temperature range. The agreement between calculated and experimental data is very good for nearly all systems of both types.
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Liquid–liquid equilibrium calculation in binary water + nonionic surfactant CiEj systems with a new Mass-Action Law model based on continuous thermodynamics
Fluid Phase Equilibria, 2005Co-Authors: C. Browarzik, D. BrowarzikAbstract:Abstract A systematic study of the LLE for a number of aqueous solutions of n -alkyl polyglycol ethers (C i E j ) with tail length i from 4 to 12 and head length j from 1 to 6 is presented. For calculation a new thermodynamic model was developed basing on the Mass-Action Law and continuous thermodynamics. Besides the micellization the self association of water is taken into account. The resulting polydisperse mixture of micelles and water associates is described by two continuous aggregation-size distribution functions depending on temperature and surfactant concentration. The Gibbs energy of the mixture is calculated by the Flory-Huggins theory with a temparature dependent parameter χ . The model is applied to 13 water + C i E j systems with LCST behavior and to the three systems water + C 4 E 1 , water + C 10 E 4 and water + C 10 E 5 with closed-loop miscibility gaps. For the former 13 systems four parameters were fitted to the experimental equilibrium data. For the systems with closed-loop miscibility gaps two additional parameters were necessary, due two the more extended temperature range. The agreement between calculated and experimental data is very good for nearly all systems of both types.
André Lefort - One of the best experts on this subject based on the ideXlab platform.
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Plasma Concentrations out of Equilibrium: N2 (Kinetic Method and Mass Action Law), Ar-CCl4 and Ar-H2-CCl4 (Mass Action Law)
Annals of the New York Academy of Sciences, 1999Co-Authors: Pascal André, Jacques Aubreton, Marie-françoise Elchinger, Pierre Fauchais, André LefortAbstract:The multi-temperature Gibbs free energy minimization (GFEM) method has been compared to the Pseudo Kinetic Method (PKM) to calculate the composition of a nitrogen plasma at atmospheric pressure. When introducing only two temperatures Te and Th with their ratio e = 2, the GFEM method overestimates by more than two orders of magnitude the density of N2+. However when calculating the kinetic rate coefficient at different temperatures the thermodynamic relationship between them and the equilibrium constant is no more fulfilled. That is why an intermediate temperature T* between Te and Th has been introduced linked to the ratio of the electrons flux to that of neutrals and e has been assumed to vary with the electron density ne, equilibrium (e = 1) being achieved either for nemax = 1022 or 1023 m-3. With nemax = 1022 m-3 the agreement between the results obtained with the PKM and the GFEM method is fairly good. That is why this latter method has been used to calculate the composition of complex mixtures of Ar-CCl4 and Ar-H2-CCl4. Below 6000 K where complex molecules exist the variation of e between 2.5 and 1.5 does not affect very much the composition which, however, depends strongly on v (v = Tv/Th)
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Comparison between Gibbs Free Energy Minimization and Mass Action Law for a Multitemperature Plasma with Application to Nitrogen
Plasma Chemistry and Plasma Processing, 1997Co-Authors: Pascal André, M'hammed Abbaoui, Roger Bessege, André LefortAbstract:This paper gives all the necessary physical equations to determine the composition and the thermodynamic in a multitemperature plasma utilizing two different methods: the first method is based on Gibbs free energy minimization and the second is based on the resolution of the Mass Action Law. The lowering terms of the ionization potential and thermodynamic properties are given for multitemperature plasma using the Debye-Huckel approximation. Numerical application is made to a nitrogen plasma.
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COMPARISON BETWEEN GIBBS FREE ENERGY MINIMIZATION AND Mass Action Law FOR A MULTITEMPERATURE PLASMA WITH APPLICATION TO NITROGEN
Plasma Chemistry and Plasma Processing, 1997Co-Authors: Pascal André, M'hammed Abbaoui, Roger Bessege, André LefortAbstract:This paper gives all the necessary physical equations to determine the composition and the thermodynamic properties in a multitemperature plasma utilizing two different methods: the first method is based on Gibbs free energy minimization and the second is based on the resolution of the Mass Action Law. The lowering terms of the ionization potential and thermodynamic properties are given for a multitemperature plasma using the Debye-Huckel approximation. Numerical application is made to a nitrogen plasma.
