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Title:
Drug synergism and dose-effect data analysis
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Publication Information:
Boca Raton, FL : Chapman & Hall/CRC, 2000
ISBN:
9781584880455

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30000004735274 RM302.3 T34 2000 Open Access Book Book
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Summary

Summary

Not since this author's bestselling Manual of Pharmacologic Calculation-long out of print-has there been a reference available for drug data analysis, and even that work did not deal with drug combinations. Although pharmacologists and most other scientists know what synergism is, mainstream textbooks tend to neglect it as a quantitative topic. Few researchers are familiar with the quantitative methodology needed to differentiate synergistic responses from the simply additive responses expected from drug combinations or a single drug's interaction with endogenous chemicals.

In Drug Synergism and Dose-Effect Data Analysis, noted pharmacologist, mathematician, and author Ronald J. Tallarida finally brings these methods to light. Drawing on statistical theory and methods but keeping the special needs of the pharmacologist in mind, he begins his treatment with dose-response relations, the statistical analysis of the data, and the models that describe them. He also offers the only modern presentation of probit and logit analysis and provides detailed calculation methods not found in typical statistics books.

Numerous examples accompany a presentation that clearly illustrates the calculations and experimental design considerations for modern drug analysis. You'll find the conceptual background, the algorithms, and new research developments. In short, Drug Synergism and Dose-Effect Data Analysis has everything you need to perform, with confidence, the quantitative analysis of dose response data.


Author Notes

Ronald J. Tallarida earned the B.S. and M.S. degrees in physics/mathematics and a Ph.D. in pharmacology. His primary appointment is as Professor of Pharmacology at Temple University School of Medicine, Philadelphia; he also serves as Adjunct Professor of Biomedical Engineering (mathematics) at Drexel University in Philadelphia


Table of Contents

Prefacep. v
The Authorp. ix
1 Combinations of Chemicalsp. 1
1.1 Introductionp. 1
1.2 Independent joint action of drugsp. 3
1.3 Additivityp. 3
1.4 Isobologramp. 5
1.5 Chloral hydrate and ethyl alcoholp. 9
1.6 The need for statisticsp. 10
1.7 The emergence of quantitative methods for studying drug combinationsp. 12
References and Suggested Readingp. 15
2 Dose-Response Analysisp. 21
2.1 Efficacy and potencyp. 21
2.2 Doses and concentrationsp. 24
2.3 Notationp. 25
2.4 Logarithmic transformationp. 26
2.5 Linear regressionp. 26
Determination of D[subscript 50] and its variance from linear regression: examplep. 31
2.6 Nonlinear modelsp. 33
Appendix 2p. 37
Referencesp. 39
3 Linear Regression: A Further Discussionp. 41
3.1 ANOVA in linear regressionp. 41
3.2 Parallel line analysisp. 44
Test for parallelismp. 44
3.3 The common slope and relative potencyp. 46
3.4 Confidence limits of the potency ratiop. 50
3.5 Weighted least square regressionp. 51
Appendix 3p. 53
Referencesp. 55
4 Calculations for Combination Drug Analysisp. 57
4.1 Experimental designsp. 57
4.2 Fixed-ratio designp. 58
4.3 Test of significancep. 60
4.4 Graphical display with standard errorsp. 64
4.5 The additive total dose: a closer lookp. 64
4.6 Changing the effect levelp. 67
4.7 Selecting the drug proportions in a combination studyp. 69
4.8 Interaction indexp. 69
Appendix 4p. 73
Referencesp. 75
5 The Composite Additive Curvep. 77
5.1 Construction of the additive curvep. 77
5.2 Test for distinguishing two regression linesp. 84
Referencesp. 89
6 Quantal Dose-Response Data: Probit and Logit Analysisp. 91
6.1 Probit analysisp. 91
6.2 Precision in probit calculationsp. 97
6.3 The composite additive probit linep. 99
6.4 Testing for synergismp. 103
6.5 Comparing the composite additive line and the actual combination linep. 103
6.6 A closer look at probitsp. 106
6.7 Testing two probit regression lines for parallelismp. 106
6.8 Constant relative potency in probit analysisp. 110
6.9 Parallel line analysis of combined drug actionp. 110
6.10 Testing for additivity: parallel constraint and probit analysisp. 112
6.11 Logit analysisp. 114
6.12 Calculations with logitsp. 116
Appendix 6 Method of Litchfield and Wilcoxonp. 119
Referencesp. 121
7 Analysis of Drug Combinations Over a Range of Drug Ratiosp. 123
7.1 Fraction plotp. 124
7.2 Testing for synergism over a range of proportionsp. 126
7.3 Combinations of acetaminophen and tramadolp. 128
Referencep. 131
8 Analysis of a Single Dose Combinationp. 133
8.1 Constant relative potencyp. 133
8.2 Variable relative potencyp. 134
Hyperbolas with different maximap. 135
Nonparallel regression linesp. 137
Referencesp. 141
9 Different Experimental Designsp. 143
9.1 Combinations of an active and an inactive drugp. 143
9.2 Site-site interactionsp. 144
Acetaminophen in Two-Site Analysisp. 145
Site-Site Analysis with Opioid Receptor Subtypesp. 147
9.3 Theory of competitive antagonismp. 147
Schild analysisp. 149
9.4 Combined inhibitory effectsp. 151
Referencesp. 155
10 Response Surface Analysis of Drug Combinationsp. 157
10.1 Additive combinations and response surfacep. 157
10.2 Super-additive combinationsp. 160
10.3 Variable relative potencyp. 161
Dose-effect relationsp. 163
10.4 Response surface analysis of morphine and clonidinep. 163
Morphine-clonidine datap. 164
10.5 Isobolar analysis or surface analysisp. 167
Referencesp. 171
11 Nonlinear Regression Analysisp. 173
11.1 Hill equationp. 174
11.2 Theoryp. 175
11.3 Sigmoid plotp. 179
Referencesp. 181
12 Statistical Concepts and Tests of Hypothesesp. 183
12.1 Hypothesis testing with the t-test: two groupsp. 183
12.2 t-test: paired datap. 185
12.3 Confidence intervalp. 187
12.4 Mann-Whitney testp. 187
Case 1p. 188
Case 2p. 189
12.5 Analysis of variancep. 189
12.6 Newman-Keuls testp. 192
12.7 Chi squarep. 194
Adjusted chi squarep. 195
Comparing two proportionsp. 195
12.8 Confidence limits of a proportionp. 196
12.9 Confidence limits for a ratiop. 197
12.10 Multiple regression (equations)p. 198
12.11 Sample size calculationsp. 200
Single proportionp. 201
Two proportionsp. 201
Two meansp. 202
Sample meanp. 202
Referencesp. 203
Computer Softwarep. 204
Appendixp. 205
Indexp. 243