Nov 1, 2018 - Harmony (Normalization) [Dm is the Harmonic Mean of Kinetic ... What Is the âDefinition of Synergyâ? ..... Slope: m; and x-Intercept: log (Dm).
Mass-Action Law Based Bio-Dynamics, Equations and Algorithms for Econo-Green Bio-R&D and for Digitalized Definitions in Drug Evaluation Guidance Ting-Chao Chou* Memorial Sloan-Kettering Cancer Center, New York, NY 10065 [*Present Address: Founder, PD Science LLC (USA) Paramus NJ 07652-1754]
A Call For Cost-Effective Bio-Medical R&D And The FDA Basic Regulatory Guideline Reform A Collection of Slides Presented in US, Switzerland, Germany, China, and Taiwan During 2014-2018, Including Those Forwarded to Regulatory Agencies and Academic Societies in US [61 PDF Slides Updated on November 1st , 2018]
Philosophy Theory Equation Algorithm Digitalized-Computer-Simulation Small-Size-Experiment Cost-Effectiveness Guidelines 1
Solving Fundamental Issues in Bio-Dynamics (BD) and Pharmaco-Dynamics (PD) A Graphic Essay
2
Basic Considerations in Biology and Medical Sciences “Mass Energy Dynamics Time Rate Space Size Shape Order Sequence Direction Logic Math Equation Algorithm Simulation Automation”
Mass & Action - Law & Order - Principle & Dynamics [Not A Random, Disoriented World] – We Shall Place Low Priority on Trivia Chasing
& Arbitrary Approaches.
In Bio-Medical Sciences: Deterministic Over Probabilistic, PD Over PK Harmony (Normalization) [Dm is the Harmonic Mean of Kinetic Constants, Kis and Kii] Equilibrium Dynamics (Doctrine of the Median) [Dm is the Dynamic Common Link] Econo-Green (MAL Two-Data Point Theory) [Dm is Universal Reference Point] The Mass-Action Law (MAL) Is the Largest Common Denominator for BioDynamics (BD) System
My “Basic Practical Questions” for Bio-medial Scientists and Governmental Regulatory Agencies 1. 2.
3. 4. 5.
6.
How to Draw A “Dose-Effect Curve” with Sound Theoretical Basis? How to Transform “Dose-Effect Curves” into “Straight Lines”? What Is the “Additive Effect” of Two Drugs? What Is the “Definition of Synergy”? [of Two Drugs or n-Drugs] What Is the “Minimum Number of Data Points” Required for A Drug Clinical Protocol in Clinical Trials? (I am Not Asking for the Minimum Number of Patients). What Is the “Minimum Number of Data Points” Required for 2-Drug Combination Synergism/Additive Effect/Antagonism Quantification in Clinical Protocol Design?
Questions Posted by Ting-Chao Chou on October 24, 2018 The Theory Is Proven Over 30 Years Ago. The Explicit Answers to The Above Have Been Provided. I Would Appreciate Your Answers, Review, Support or Valid Rebuttal.
4
My “Personal Basic Concept” in Biomedical Sciences What? The Fundamental Principle of Biology & Medical Sciences Follow the Mass-Action Law (MAL) Dynamics. e.g., Biodynamics (BD) and Pharmacodynamics (PD).
Why? Our World Is Not Random or Dis-oriented: Physical, Chemical & Mathematical Rules How? Doctrine of the Median [DoM] The Median-Effect Equation [MEE] The Combination Index Equation [CIE]
The Dose-Reduction Index Equation [DRIE] The Receptor Binding Distribution Equation [Ki/IC50 Eq.] Algorithms – Diagnostic Plots – Automation Who?
Chou and Henderson-Hasselbalch, Hill, Michaelis-Menten, Scatchard, etc.
When? 20th -21st Centuries Who Indicated “Personal Appreciation” of MAL Theories? – Four Nobel Laureates: Sir Hans A. Krebs, James D. Watson, Carl F. Cori and Andrew V. Schally (see slides below)
and >30,000 Bibliometric Citations, and >30,000 Downloads of CompuSyn Software by Scientists from 127 Countries or Territories
Biology Complexity Diversity ----------------------------Simplicity Integration -------------------------The Mass Action Law & “Dynamics” BioDynamics (BD): Doctrine of The “Median”
PharmacoDynamics (PD): Median-Effect Eq. & Combination Index Eq. Mass & Action: “Dose” & “Effect” Are “Interchangeable” All Dose-Effect “Curves” Can Be Transformed Into “Straight Lines”
IN SEARCH OF TRUE “SIMPLE” DEFINITIONS
“GENERAL BIO-DYNAMICS”: m
Fa/Fu = (D/Dm)
“SYNERGY”: CI < 1 A Dedication to the Synergy Keynote Forum – 2018 Bonn, Germany March 9 – 10, 2018
[Is This Normal? Is This Sustainable? Something Must Be Wrong!] Drug Evaluation is Unreliable, and High Risk Endeavor/Investment. Why?...
NAD: New Drug Applications NME: New Molecular Entities
8
Chou TC Advocate BioMedical Definitions & Guidelines Reform For: “Dose-Effect Curve”, “Synergy”, “Valid Model”, “PD”, “DDI” & Clarify What is FDA’s “ExposureResponse” & “MIDD”? Biomedical
Keynote Forum
Communities in the World, (and NIH/ASPET/AACR, Not Only FDA)
Are to Bear the Responsibility! For Patient’s Legal Rights, Chou had-------1. Public Hearing at FDA. Silver Spring, MD 10.2.2017, and 2. Public Comments to Regulations.gov and to FDA/CDER/CBER/OCP 10.7.2017; 11.22.2017; 5.10, 2018 Open Letter to AACR. 8.7.2017; 1.17.2018 Open Letter to ASPET. 10.9.2017
3. 4. Open Letter to NIH & NIH Director. 8.1.2017; 1.14.2018
[The “Quantitative, Digital & Computerized” Econo-Geeen Biomedical R&D Is Overdue, Please See Slides Below]
9
New Conceptual Path Meet with Unqualified Resistance and Very Late Acceptance
System Analysis
with “Combinatorial, Pattern Analysis of
the Mass-Action Law” with “Mathematical Induction – Deduction” to Derive the Unified General Median-Effect Equation (via >300 Equations), as Algorithm, for Computer Simulation. Then, Using the “Unified Theory” as the “Largest Common
Denominator” to Simplify the Complex Biological Systems, for “Dose” & “Effect” Pharmacodynamics (PD) and Biodynamics (BD). This Unique System Analysis/Math Approach Has No Precedence in Bio-Medical Sciences It Took Over 3 Decades to Begin to Have Peers’ Broad Recognition and Acceptance.
10
HOW TO MAKE COMPLEXITY SIMPLE? THE POWER OF MATHEMATICAL INDUCTION AND DEDUCTION [LET’S APPLYING IT TO THE “BIOLOGICAL SYSTEM-ANALYSIS”] (USING THE UNIFIED GENERAL DYNAMICS THEORY OF THE MASS-ACTION LAW AS THE LARGEST COMMON DIVIDER FOR SIMPLIFYING THE COMPLEX BIOLOGICAL SYSTEMS)
Q. 1+2+3+4….+ 6,789 = 23,048,655 [RIGHT OR WRONG ?]
A. IT IS EASY. I CAN ANSWER IT IN 3 MIN, WITH A PEN & A PIECE OF PAPER [OR IN 10 SEC, WITH A POCKET CALCULATOR]. Q. HOW?
[YOU CAN SOLVE IT IN VARIOUS ELABORATED OR SIMPLE WAYS], BUT 𝑛
A. BECAUSE..
𝒏 𝒏+𝟏 = 𝟐
𝑛=1
=
6789 × 6790 = 23,048,655 2
11
“Trend, Apps & Impacts” of the Mass-action law based Theories:
BD & PD Waiting for Academic Communities/Societies, NIH, and FDA To Accept (or To Reject with Valid Reasons) [These are Basic and Fundamental Issues in Bio-Medical Sciences] [ For Accountability & Credibility, These Issues Need To Be Resolved]
Philosophy Theory Equation Algorithm Digitalized-Computer-Simulation Small-Size-Experiment Cost-Effectiveness Guidelines
12
27785
28000
Total Number of Scientific Citations During 1981-2017
26000
Based on “Google Scholar Citations – Ting-Chao Chou”
24000
[From a Lab with an Average of Only 5 Members including a Ph.D. 3 Associates and a Secretary. I Never Received a Research Grant Support for The Theoretical Work from the “Peer Review” System!] [86% of My Citations Are Since 60-year Old!] [Received 10,432 Citations Since My Retirement 5 Years Ago]
20000 18000 16000
12000 10000
18182
70 years old 16744
6000
MEE Theory (in 1976) & CI Theory in
4000 2000
331 418 60 124 185 255
15350
Pharmacol Rev
14085 13021 11908
10975 9764 8734
60 years old
8000
21326 19671
Example & Evidence for The EconoGreen Bio-Med R&D. ----------------------------------“Peer Review”? How? Who? Fair? Encouraged the “Me-Too” Research.
14000
23081
EconoGreen Reform
[As of 11.1.2018 Total Citations: 30,381. 452 Publications] , 40 US Patents. Story:
22000
7753
6822 6072 5310 4802 4285 3792 50 years old 3329 2907 2582 2221 1863 1501 1190 900 541 692
2017
2016
2015
2014
2013
2012
2011
2010
2009
2008
2007
2006
2005
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
1987
1986
1985
1984
1983
1982
0 1981
Number of Cumulative Citations
25156
14
Ting-Chao Chou – Google Scholar Citations [As of 10.26.2018 (472 publications)]
15
A Biomedical R&D and Regulation “Revolution” Is on the Horizon? What, Why, and How • • • • • •
The Mass-Action Law (MAL) Based Silico Quantitative Biology New Pharmacodynamics (PD) and Biodynamics (BD) Bio-Informatics Quantitative Data Generation and “Digitalized Conclusions” “Econo-Green” Determinations of Efficacy and Toxicity MAL Theory Based “Experimental Design” and “Data Analysis” MAL Theory Based Small Size Study with Computer Simulation Using “Very Few Data Points” in Clinical Protocol Design and Data Analysis, and in Animal Experimental Evaluations ---------------------• The PD Theory is Proven. Its Saving Time & Efforts, and Conserving Research Resources Would Be >$100’s of Billion Dollars! I Open-Mindedly Welcome Any Valid Challenge! (Pro or Con) or Providing a New Better Theory. 16
Chou -Talaly CI Theory (1984) 4,582 citations In 1,112 journals 11.1.2018
17
Scopus Analysis: Citations of TC Chou’s Publications by papers in Subjects/Disciplines 8.29.2018 (In >1,112 Journals)
18
Scopus Analysis: Chou TC’s Publications Cited by Papers from Institutional Affiliations 8.29.2018
19
“Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies”
11.1.2018 Citations
CHOU TC, PHARMACOLOGICAL REVIEWS, 58: 621-681, 2006
Times Cited: 2,686 (1,956 Citations in 821 Journals)
20
Major Problems of Contemporary BioMedical Sciences (The Chou’s Personal (Critical) Views)
Chasing Trivia and Empirical Phenomena but Neglect the Fundamental Principles. BD and PD Theory of the “Mass-Action Law” Are Poorly Appreciated. Do Not Know How to Draw a “Dose-Effect Curve” with Sound Theoretical Basis. Do Not Understand the “Additive-Effect” of Two Drugs. Do Not Have Clear (Mathematical) “Definition of Synergy” in Drug Combinations. Emphasizing “PK” and Neglecting “PD” in Drug Evaluations Regulations by FDA. Complacency to Status Quo and Resistance to New Concepts and New Innovations. Too Much “Me-Too” & “Low Quality” Research and Papers. [43% of 58 Million Scientific Papers in the Past Century Received Zero Citation] “Peer Review” with Interest Groups & Lack of Expertise that Hinders the Progress. 21
PD’s “Model” Is The Nature’s Mass-Action Law [MAL] PD Is The Fundamental “Dose” and “Effect” Mathematical Relationship [PK is Empirical Observational Science that Has “No Model”]. [PK is Just the Intermediary n-Steps (ADME) within the PD Domain]. [PK Is An Endless Sink of Research Resources].
PD
(Mass-Action Law)
Unknown PK (Intermediary, “n steps”) Distribution
Drug
Metabolism
Absorption
Effect
Distribution
Excretion
Chou, TC. Comments to NIH/ASPET/AACR & FDA, 2017-18
PD Science, LLC (USA)
“PD” Should Have Higher Priority than “PK” in Drug Evaluations and Regulations ! PD to Avoid Wasting Time, Effort, and Resources. PD trims the R&D Attrition Rate by “Optimized PD Practice”
Where is FDA’s “Definition for PD”? 22
New Emphasis on Pharmcodynamics (PD) Over Pharmacokinetics (PK) [Presented at Drug Development Summit, Zurich, Switzerland, by Chou TC 6.08.2011;
Am J Cancer Res 1(7): 925-954, 2011]
PD
PK
Mode of action
What drug does to the body
What body does to the drug
Characteristics
Mainly vary dose (fixed time) Single Unified Theory of Mass-Action Law
Mainly vary time (fixed dose) Observational Multi-Factorial Mix
The median-effect principle of the mass-action law
Empirical phenomenal /observations
Rigorousness
Explicitly derived equations
Empirically perceived formula
Applications
Physico/chemical quantitative parameters in Vitro & in Vivo
Probabilistic empiric parameters in Vivo Only
Parameters & Constants [Defined PD And Empirical PK]
Dm, m, r, CI, DRI, IC50, Km, Ki, Ka and Kd Competitiveness, Exclusivity, Synergism, Antagonism [Mass-action parameters for potency, shape, dynamic order, and interaction indices]
t½ , Cmax, Cl, AUC, Vdis Absorption, Distribution, Metabolism, Excretion [Measurement of Parameters without direct physicochemical bearing]
Determining Efficacy
Yes
No
Determining Toxicity
Yes
No
What it takes to be a good drug
Help proper use of a drug
Items
Principle
Determinant for
23
“Synergy Definition” for Drug Combination (Controversy for Over 100 Years)
•
Drug Combination: Widely Used in Cancer , AIDS & Chinese Traditional Medicine…
•
Synergism:
•
Combination Index (CI): Chou & Talalay, Adv. Enz. Regul. 22: 27-55, 1984
•
•
20 Different Definitions for Synergy None Supports the Others ! Only CI Method is Quantitative !!
[Computerized Quantitation & Simulation] CI 1, Antagonism
If No Clear Definition for Synergy: NIH, FDA, USPTO and Journal Editors have No Basis to Judge or to Regulate the “Synergy Claims”
Challenge:
― The Dispel of the Century-Old Controversy of “Synergy Claims”
The Chou-Talalay CI Definition: The Most Cited Drug Combo Method of All Time
24
Trends of Drug Combination Methods for Synergy Determination, 1900- August 2018* Thomson Reuters Web of Science Citation Database
Trend of Citation
Method, and Reference Source
Total Citations
2014 2015 2016 2017 2018*
These Are Public Facts. Why FDAs Still DO Not Accept CI? Drug Combination “Synergy” Still Undefined? Does Combo Therapy Used in Treating Cancer and AIDS?
A. Chou, TC & Talalay, P Adv. Eng. Regul. 1984; 22:27-55 [MEE & CI Theory] B. Chou, TC Pharmacol. Rev. 2006;58: 621-681 [MEE & CI Review] C. Chou TC Cancer Res. 2010; 70: 440-446 [CI Perspectives] D. Berenbaum, MC Pharmacol. Rev. 1989; 41: 93-141 E. Bliss, CI Ann. Appl. Biol. 1939; 26: 585-615 F. Greco, WR et al Pharamacol. Rev. 1995; 47: 331-385 G. Steel GG & Peckham MJ Int. J. Radiant. Oncol. BioPhys. 1979; 5: 85-91 H. Tallarida, RJ J. Pharmacol. Exp. Ther. 2001; 298: 865-872 I. Elion GB, Singer S & Hitchings GH J. Biol. Chem. 1954; 208: 477-488 J. Prichard, MN & Shipman C Jr Antiviral Res. 1990; 14: 181-205 K. Webb J.L. Acad. Press. 1963; 1: 66-79, 488-512 L. Loewe, S Pharmacol. Rev. 1957; 9: 237-242
Since Publication
Average Citations per
year
332
311
310
332
208
4,604
136.8
211
272
308
318
183
1,939
166.2
177
239
288
318
184
1,466
191.2
43
40
50
39
26
1,070
37.3
77
68
106
87
67
993
12.6
58
73
81
74
44
878
38.7
16
19
18
22
7
751
19.4
38
46
36
14
8
472
17.1
4
7
3
7
3
469
28.1
25
27
35
30
7
433
7.9
9
9
7
11
7
344#
5.4
5
3
2
3
2
127
2.1
*Based on Thomson Reuters Web of Science all database, as of August 29, 2018. (Citation numbers are higher in Google Scholar Citations). #Based on Google Scholar Citations, as of August 29, 2018 (for Books).
25
Tales of Two Anti-HIV Clinical Trials AZT + 3TC
AZT + INFα
Authors
J.J. Eron et al. (9 authors + Northern Am. HIV Working Party
D. Mildvan et al. (21 authors)
Publication
N. Engl. J. Med. 333: 1662-1669, 1995
Antiviral Therapy 1(2): 77-88, 1996
Journal Impact Factor
28.5
3.1
Number of Patients
366
36
Surrogate Marker
CD4+ , HIV-RNA
Treatment Design What They Have Proved
Fractionated Repeated Doses AZT Single Dose, 3TC 2 Doses “Combination Effect is Greater than Each Drug Alone”
Not Possible to Claim Synergism A+B > A, A+B > B (p1 year
$3,000
Expensive Trials [$ millions,Vary]
$200
[cells and chemicals]
[nude mice]
> 65
> 36
[cells]
[nude mice] [Chou-Talalay method]
[vary based on accuracy of end-point determination] [Chou-Talalay method]
16*
10
10
Very Easy
Not Difficult
Difficult
[Rarely properly done in the past]
Use Surrogate Markers, Fractional Doses and Scanning
> 2 x 106
[But frequently not done properly in the past]
29
*Practical increase of data points in vitro due to simplicity, low cost, and no ethical, legal restrictions.
Median Effect Equation (T.C. Chou, J Theor Biol 59: 253-276, 1976) [The 1st Law of MAL Based PD/BD]
Unified General Theory for Drug Dynamics
[Doctrine of The Median]
Hyperbolic (1st Order) m = 1, or Sigmoidal (Higher Order) m>1 (or m 1 Favorable dose reduction < 1 Not favorable dose reduction
,
Retaining Efficacy Decreasing Toxicity Therapeutic Advantage
33
The Unified PD/BD Theory of The Mass-Action Law Derivation of Major Biochemical and Biophysical Equations from the Median-Effect Equation [Chou T.C. Pharmacol. Rev. 58: 621-681, 2006]
Henderson-Hasselbalch equation
log [H+] = log Ka + log [HA] [A–]
pH = pKa + log
fa = fu
[A–] [HA]
( ) D Dm
m
The Median-Effect Equation Chou, J. Theor. Biol. 59: 253-276, 1976
“Doctrine of the Median” for Biodynamics (BD): Dm: Half Affected Km: Half Saturated Ka: Half Ionized K: Half Occupied Kd: Half Bound, Half Free
fa /(1–fa ) = (D/Dm)m fa = [1+(Dm/D)m ]–1 log [( fa/(1–fa)] = m[log(D) – logDm] log [( fa)–1–1]–1 = m log(D) – m logDm fa/fu = D/Dm
Michaelis-Menten equation (Lineweaver-Burk Plot) v/Vmax = [1+(Km/S)]–1
[The Unified MedianEffect Equation Is “Derived” (Proven) from the Mass-Action Law. The Major Four Equations in Biochemistry and Biophysics Are the Special Cases of the Unified PD Theory].
Hill equation
Scatchard equation
log [v/(Vmax –v)] = n log(S) – log (K)
[L]b n[M]t [L]b = – [L]f Kd Kd
34
35
Blogs Home Integrative Biology Blog Integrative Biology Blog RSS
HOT: one equation to lead the way to greener biomedical sciences 05 May 2011
By Francesca Burgoyne In this HOT Perspective article Ting-Chao Chou from the Memorial Sloan-Kettering Cancer Center, New York presents his vision for a new era of smarter, greener biomedical research and drug discovery. The algorithm of the median-effect equation based on the mass-action law, along with experimental design and computer simulation, should allow a significant reduction in the number of data points required to yield useful bioinformatics on the relationship between dose and effect. He poses that a theoretical minimum of a mere two data points are required to construct dose-effect curves – if they are accurately determined. This unified theory, he believes, should pave the way for more efficient, cost-effective research and ethical clinical trials. This HOT article received glowing reports from our referees and is featured on the front cover of our latest issue – Issue 5. Why not take a look – it’s currently free to access:
The mass-action law based algorithms for quantitative econo-green bio-research Ting-Chao Chou Integr. Biol., 2011, 3, 548-559 [Published by Royal Society of Chemistry, Cambridge, UK] DOI: 10.1039/C0IB00130A 6177480 36
Algorithm for Computerized Simulation of Synergism, Additivism and Antagonism of the Effect of Multiple Drugs The Median Effect Equation (1) fa/fu = (D/Dm)m (2) Log( fa/fu) = mlog(D) – mlog(Dm) (3) fa = 1/[1+(Dm/D)m] (4) Dx = Dm[fa /(1–fa )]1/m
D = Dose fa = fraction affected fu = fraction unaffected Dm = median-effect dose m = slope, Hill-type coefficient or kinetic order
(5) CI = (D)1 + (D)2 = 1 + 1 (Dx)1 (Dx)2 (DRI)1 (DRI)2
CI : Combination Index CI = 1 (summation) < 1 (synergism) > 1 (antagonism)
(Dx)1,2 = (D)1+ (D)2 and (D)1/(D)2 = P/Q (D)1 = (Dx)1,2 x P/(P+Q) (D)2 = (Dx)1,2 x Q/(P+Q) [For Multi-Step Logics & Integrated Analysis]
DRI: Dose-Reduction Index (D ) (D ) (DRI)1 = x 1 , (DRI)2 = x 2 (D)1 (D)2 For n Drug Combinations:
General Theory for Bio-Interactions [Chou. Pharmacol Rev 58: 621-681, 1984]
n
CI =
J=1
(D)j (Dx)j
[General Applications: This Unified Algorithm is Independent to Drug Ratio, Units, Mode of Actions, and Mechanisms. It is Valid for n Drugs or Entities Combination Interactions 37
Auto-generated Diagnostic Plots for Drug Combination Dynamics by CompuSyn: Geometric Transformations and Algorithm Based, Simulated, Digitalized, Indexed Conclusions in One Second. (Chou-Talalay Plot)
(Chou-Chou Plot)
“New Digital Bio-Informatics”
(Chou-Martin Plot)
[Chou TC. Pharmacol. Rev. 58: 621-681, 2006; Integr. Biol. 3: 548-559, 2011]
[All These Four Diagnostic Plots can be generated within One Second, Following the “Dose” & “Effect” Data Entries].
38
Quantitative-Analysis of Dose-Effect RelationshipsThe Combined Effects of Multiple-Drugs or Enzyme-Inhibitors [The Combination Index Theorem Citations as of 11.1.2018]
CHOU, TC & TALALAY, P ADVANCES IN ENZYME REGULATION, 22: 27-55, 1984*
Times Cited: 5,890; (4,582 Citations in >1,112 Journals)
*Elsevier News Release: “Chou & Talalay Article from 1984 Makes History” (3.16.2016) 39
[News Release, March 16, 2016]
Chou & Talalay Paper from 1984 Makes History https://www.journals.elsevier.com/advances-in-enzyme-regulation/news/-chou-talalay-paperfrom-1984-makes-history Many FDA Officers still Refuse to Accept this Proven MAL-PD CI Theory, 34 Years Later, in One of the most cited papers 2018! -- T.C.Chou Published in 1984, the manuscript “Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors” by Ting-Chao Chou and Paul Talalay has become one of most cited articles in all fields. With 3,520 citations, it is not only the most cited article in Advances in Biological Regulation, but also one of the most cited articles (being in the top 1% of most cited articles) in the field of Biochemistry, Cancer Research, Molecular Biology and Genetics (Scopus, 16thMarch 2016). Here is what Ting-Chao Chou, first author of the manuscript tells us: “Over 31 years ago, Prof. George Weber of Indiana University invited Prof. Paul Talalay (JHU) and me (MSKCC) to give a symposium talk sponsored by Eli Lilly, in conjunction with Advances in Enzyme Regulation. My talk was very much impressed by Professor Carl F. Cori of Harvard (Nobel Laureate of Medicine 1947). His vision has proven to be extremely insightful and accurate. The paper in Adv. Enz. Regul. 22:27-55, 1984 by Chou & Talalay has become among the most cited and the most broadly cited theoretical papers of all time in all fields.” It is our pleasure to celebrate this milestone for our journal and for this occasion we have provided free promotional access to the article for 6 months on ScienceDirect.
40
A “Constant-Ratio” Econo-Green Experimental Design Showing the Outlay of Two Drugs for Drug Combination Analysis in Vitro [Using Only 16 Data Points, (3X5 +1 = 16) in duplicates or triplicates]*
Simple and Efficient ConstantRatio Diagonal Combo Design (Recommended)
[The “Non-Constant Ratio Design” can also be used for quantitative Synergy determination. But No automatic computerized simulation can be done]
*For animal or clinical trials, the practical minimum is 10 data points (3X3 +1 = 10), by removing the lowest and highest doses in this scheme. Each Dose has 4-6 or more animals or patients, depending on the measurement need, in vivo with 1.3-1.5 fold serial dose dilutions instead of 2-fold dilutions in vitro. [The Recommended Practical Minimum Number of Data Points for Two Drug Combinations In Vitro, In Animals and In Clinical Trials: 16, 10, and 10, respectively]
41
[The Concept of Isobologram has over 70 years of history, but no theoretical algorithm until CI Equation in 1984. The old method for Isobologram used graph paper for extrapolations and interpolations and will take 30 min to 1 hour to construct]. Fa-CI plot and Isobol are two-sides of the same coin. (i.e., same conclusion). But FaCI plot is more practical to use for different effect levels.
Combination Data Points: On Diagonal Line (point a) indicates Additive Effect. On Lower-Left (points b.c.) indicate Synergism, On Upper-Right (points d.e.) indicate Antagonism. This Graph is for Visual Diagnosis at ED50 effect level or Other effect levels.
Isobol Equation is only a special case of the ChouTalalay’s CI Equation (i.e., when CI=1). Now the Isobologram can be generated in less than one second by using PD algorithm based CompuSyn software. 42
CompuSyn For “PD” of Single Drug and Drug Combinations [ An “One Second” Automated Data Analysis Based on The Mass-Action Law] A Computer Program for Quantitation of Synergism and Antagonism in Drug Combinations, and the Determination of IC50 , ED50 and LD50 Values.
By Ting-Chao Chou (MSKCC)
and Nick Martin (MIT) Published and Distributed by ©Copyright
ComboSyn, Inc.
2004, On Market (2005-2012)
Offered for Free Download as A Donation to the Biomedical Communities upon Registration: Since 8/1/2012 [As of 11.1.2018: 30,729 Downloads by Bio-Scientists from 127 Countries or Territories ]
http://www.combosyn.com
– PD Science, LLC 43
[Chou TC. Pharmacol. Rev. 58:621-681, 2006]
[The Theoretical Basis for the Future Drug Combination in High Throughput Robotic Data Analysis. e.g., for the Traditional Chinese Medicine, Etc.]
44
5-Drug “Polygonogram”
[This graph was featured on the front cover in Integrative Biology. 3: 548-559, 2011 (May)]
[Cancer Chemotherapy Combination & AntiHIV Cocktail Design]
With 5 Different Anti-Cancer Mechanisms
“Mechanisms” Can Not Predict Synergy Quantitatively! Polygonogram “Projects the Outcomes” Visually and Semi-quantitatively. 45
Journal Inauguration First Article September 23, 2014 Basel, Switzerland
46
Typical “Diagnostic Fa-CI Plots” for Anti-HIV Agents Combinations
[Chou TC. Pharmacol. Rev. 58: 621-681, 2006] {These data were obtained in collaboration with MGH, Harvard Medical School}
47
Quantitative (CI) and Qualitative Presentations of Synergy [CI is the Key For All]
[Chou TC. Pharmacol. Rev. 58: 621-681, 2006]
48
Polygonogram for Cocktail Design Using Chou-Talalay’s CI Method & CompuSyn Software
Mechanism Usually Can’t Predict Synergism. Even If Predicted, It Is Not Quantitative!
“Polygonogram” of Chou Allows Simple Tentative Projections for More Drug Combinations
49
Computerized CI Simulation of Synergism/Antagonism by CompuSyn [The Practical , Econo –Green & “Quantitative Bio-Informatics”]
Primary Questions:
Are there any synergism? How much synergism? Synergism at what dose levels? Synergism at what effect levels? What the exhibited isobologram looks like? How many folds dose reduction for each drug as results of synergism?
Other Questions:
These Questions Are What the Combination Index Equation (CIE) & Software Answered.
[How Many of These Questions Can Be Answered by the Current FDA “Guidelines”? Or “PK-PD Model”, Or Any Other Methods?]. Please Answer.
Optimal combination ratio (1:1; 3:1; 1:3 which better?) Schedule dependency (Simultaneous, A follows B, B follows A) Selectivity of synergism (Target vs Host) Condition directed synergism (Temperature, Pressure, pH, Oxygen Tension ..)
50
The Mass-Action Law [MAL] The Fundamental Physico-Chemical & Mathematical Principle
“Doctrine
of the Median” The General Applications [In >1,112 biomedical Journals]
Defines Pharmaco-Dynamics for Single Drug & Drug Combinations Provides Algorithms for Computerized Simulation Allows Efficient Designed Experiments, Using Fewer Data Points Facilitates Bio-Medical ‘Econo-Green’ R&D Reform, Improve Regulatory Guidances 51
Web References T.C. Chou Web Sites Thomson-Reuters
Web of Science: http://www.researcherid.com/rid/B-4111-2009 Google Search: Ting-Chao Chou Ting-Chao Chou - Google Scholar Citations Wikipedia: Ting-Chao Chou www.Combosyn.com [Offered “CompuSyn” for Free Download upon Registration beginning 8.1.2012, by PD Science LLC (USA)] (As of 11.1.2018, a Total of 30,729 Downloads by Scientists in 127 Countries or Territories Worldwide). 52
53
Appendix Slides Supplementary Information
54
A Visionary Letter from Sir Hans A. Krebs) of Oxford, Nobel Laureate of Medicine (1953). (This Aerogram Was Received Several Weeks after Article Publication) (This Article Took 2.5 Years to Publish while Chou as a Junior Faculty; Rejected by Two Journals, Twice, before Publishing in the Third Journal) (This Article Set The Foundation of Chou’s >40 Years of Theoretical Career)
[Chou
TC. Mol. Pharmacol. 10: 235-247, 1974] (Derivation of Over 100 Reaction Rate Equations)
Date
[Letter from James D. Watson to Ting-Chao Chou]
Identifier
Location
1974- JDW/2/2/26 Collection JDW: James 10-09 3/65 D. Watson Collection (1895-2011)
A Modest Letter Saved in Prof. James D. Watson’s Repository, Harvard University. Nobel Laureate of Medicine 1962 for the DNA Double Helix. [This Archive Doc. was found by Chou in the Web, 40 years later, in 2014]. [Chou TC. J. Theor.. Biol. 59: 253-276, 1976] (MS) (Derived the Median-
Effect Equation & Plot. Later becomes the Unified General Theory of the Mass-Action Law, the foundation for PD and BD)
Visionary Letter from Professor Carl F. Cori (1896-1984) of Harvard, Nobel Laureate of Medicine 1947.
[This article received 1 citation in 1st year (self-citation), and 5 citations in 2nd year]
[ Chou TC & Talalay P. Adv. Enz. Regul. 22:27-54, 1984] [Introduced The Combination Index Theorem and software; Now Received 5,890 Citations in 1,112 Journals, which “Makes History”]; Elsevier News Release 3.16.2016)
Letter from Professor Andrew V. Schally [Nobel Laureate of Medicine, 1977] to Ting-Chao Chou [MSKCC] on November 6th, 2006 “I should greatly appreciate receiving a reprint of your paper published in Cancer Research 65: 9445-9454, 2005.” , via parenteral or oral route ]
Chou TC et al. Title: “Therapeutic cure against human tumor xenograft in nude mice by a microtubule stabilization agent, Fludelone, via parenteral or oral route”
This 61-Page (45,530 Words) 2006 Article Received 2,686 Citations in 821 Bio-Medical Journals Worldwide, as of 11.1.2018.
[The most broadly cited pharmacological article of all time]
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[The End]
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