Kenakin A Pharmacology Primer

Theory, Application and Methods
3. Auflage 2009
ISBN: 978-0-08-092333-8
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 416 Seiten

This successful guide assists scientists trained in molecular biology and related fields who now need to know the basic theories, principles and practical applications of pharmacology. This latest edition continues the tradition of better preparing researchers in the basics of pharmacology. With expanded hands-on exercises and the addition of Pharmacokinetics coverage, new human interest material including historical facts in pharmacology and a new section on therapeutics that will help readers identify with diseases and drug treatments.
The ideal book for researchers in drug discovery who have seen their role shift from 'individual' to 'team player' where that team includes chemists, biologists, and others with strong, but varied, science backgrounds who must now work together toward their common pharmacology goal.
At GlaxoSmithKline, a pharmaceuticals world-leader, Terry Kenakin regularly teaches a course for their research scientists and has drawn on his experience to create a pharmacology primer.
*New - Latest coverage of the chemistry of drugs including expanded coverage of the pharmacokinetic discussion of druglike properties -- Increases reader understanding of necessary ADME (Absorption, Distribution, Metabolism, and Excretion) properties and increases the rate of drug approval and acceptance.
*Context - Unique discussions on various drug discovery teams and the role of the chemist on those teams -- Promotes the understanding of these expanding roles and responsibilities and how to maximize the effective contributions of each matrix team member.
*Real-world learning - There are hands-on exercises, with extensive answers, utilizing real data on structure activity relationships; utilization of pharmacological principles to make general statements about how changes in structure lead to changes in drug activity. + hands on exercises with extensive answers on Pharmacokinetics -- Stengthens practical application and understanding of core concepts and principles.
*Study sections are organized with ASPET (American Society for Pharmacology and Experimental Therapeutics)and other international organizations -- Ensures that learning follows professional industry standards.


Terry P. Kenakin is the recipient of the 2008 Poulsson Medal for Pharmacology awarded by the Norwegian Society of Pharmacology for achievements in basic and clinical pharmacology and toxicology. He has also been awarded the 2011 Ariens Award from the Dutch Pharmacological Society and the 2014 Gaddum Memorial Award from the British Pharmacological Society. Having been involved in drug discovery for over 30 years, his interests include the optimal design of drug activity assays systems and quantitative drug receptor theory. He is a member of numerous editorial boards as well as Editor-in-Chief of the Journal of Receptors and Signal Transduction and Current Opinion in Pharmacology. In addition, Dr. Kenakin has authored numerous articles and has also written a number of books on pharmacology.

Autoren/Hrsg.

Kenakin, Terry P.

Kenakin, Terry

Inhaltsverzeichnis

1;Front Cover;1
2;A Pharmacology Primer: Theory, Applications, and Methods;4
3;Copyright Page;5
4;Dedication Page;6
5;Contents;10
6;Preface;16
7;Preface to the Second Edition;18
8;Preface to the First Edition;20
9;Chapter 1 : What Is Pharmacology?;22
9.1;1.1. About This Book;22
9.2;1.2. What Is Pharmacology?;22
9.3;1.3. The Receptor Concept;24
9.4;1.4. Pharmacological Test Systems;25
9.5;1.5. The Nature of Drug Receptors;27
9.6;1.6. Pharmacological Intervention and the Therapeutic Landscape;28
9.7;1.7. System-Independent Drug Parameters: Affinity and Efficacy;29
9.8;1.8. What Is Affinity?;31
9.9;1.9. The Langmuir Adsorption Isotherm;33
9.10;1.10. What Is Efficacy?;35
9.11;1.11. Dose-Response Curves;36
9.11.1;1.11.1. Potency and Maximal Response;37
9.11.2;1.11.2. p-Scales and the Representation of Potency;38
9.12;1.12. Chapter Summary and Conclusions;39
9.13;1.13. Derivations: Conformational Selection as a Mechanism of Efficacy;40
9.14;References;40
10;Chapter 2 : How Different Tissues Process Drug Response;42
10.1;2.1. Drug Response as seen through the "Cellular Veil";42
10.2;2.2. The Biochemical Nature of Stimulus-Response Cascades;44
10.3;2.3. The Mathematical Approximation of Stimulus-Response Mechanisms;47
10.4;2.4. System Effects on Agonist Response: Full and Partial Agonists;47
10.5;2.5. Differential Cellular Response to Receptor Stimulus;50
10.5.1;2.5.1. Choice of Response Pathway;50
10.5.2;2.5.2. Augmentation or Modulation of Stimulus Pathway;52
10.5.3;2.5.3. Differences in Receptor Density;53
10.5.4;2.5.4. Target-Mediated Trafficking of Stimulus;53
10.6;2.6. Receptor Desensitization and Tachyphylaxis;56
10.7;2.7. The Measurement of Drug Activity;57
10.8;2.8. Advantages and Disadvantages of Different Assay Formats;57
10.9;2.9. Drug Concentration as an Independent Variable;58
10.9.1;2.9.1. Dissimulation in Drug Concentration;58
10.9.2;2.9.2. Free Concentration of Drug;59
10.10;2.10. Chapter Summary and Conclusions;60
10.11;2.11. Derivations;60
10.11.1;2.11.1. Series Hyperbolae Can Be Modeled by a Single Hyperbolic Function;61
10.11.2;2.11.2. Successive Rectangular Hyperbolic Equations Necessarily Lead to Amplification;61
10.11.3;2.11.3. Saturation of Any Step in a Stimulus Cascade by Two Agonists Leads to Identical Maximal Final Responses for the Two Agonists;61
10.11.4;2.11.4. Procedure to Measure Free Drug Concentration in the Receptor Compartment;61
10.12;References;62
11;Chapter 3 : Drug-Receptor Theory;64
11.1;3.1. About This Chapter;64
11.2;3.2. Drug-Receptor Theory;65
11.3;3.3. The Use of Mathematical Models in Pharmacology;66
11.4;3.4. Some Specific Uses of Models in Pharmacology;66
11.5;3.5. Classical Model of Receptor Function;68
11.6;3.6. The Operational Model of Receptor Function;69
11.7;3.7. Two-State Theory;70
11.8;3.8. The Ternary Complex Model;71
11.9;3.9. The Extended Ternary Complex Model;71
11.10;3.10. Constitutive Receptor Activity;72
11.11;3.11. The Cubic Ternary Complex Model;74
11.12;3.12. Multistate Receptor Models and Probabilistic Theory;74
11.13;3.13. Chapter Summary and Conclusions;76
11.14;3.14. Derivations;76
11.14.1;3.14.1. Radioligand Binding to Receptor Dimers Demonstrating Cooperative Behavior;76
11.14.2;3.14.2. Effect of Variation in an HIV-1 Binding Model;77
11.14.3;3.14.3. Derivation of the Operational Model;78
11.14.4;3.14.4. Operational Model Forcing Function for Variable Slope;78
11.14.5;3.14.5. Derivation of Two-State Theory;79
11.14.6;3.14.6. Derivation of the Extended Ternary Complex Model;79
11.14.7;3.14.7. Dependence of Constitutive Activity on Receptor Density;80
11.14.8;3.14.8. Derivation of the Cubic Ternary Complex Model;80
11.15;References;80
12;Chapter 4 : Pharmacological Assay Formats: Binding;82
12.1;4.1. The Structure of This Chapter;82
12.2;4.2. Binding Theory and Experiment;82
12.2.1;4.2.1. Saturation Binding;84
12.2.2;4.2.2. Displacement Binding;86
12.2.3;4.2.3. Kinetic Binding Studies;90
12.3;4.3. Complex Binding Phenomena: Agonist Affinity from Binding Curves;91
12.4;4.4. Experimental Prerequisites for Correct Application of Binding Techniques;94
12.4.1;4.4.1. The Effect of Protein Concentration on Binding Curves;94
12.4.2;4.4.2. The Importance of Equilibration Time for Equilibrium Between Two Ligands;95
12.5;4.5. Chapter Summary and Conclusions;96
12.6;4.6. Derivations;97
12.6.1;4.6.1. Displacement Binding: Competitive Interaction;97
12.6.2;4.6.2. Displacement Binding: Noncompetitive Interaction;97
12.6.3;4.6.3. Displacement of a Radioligand by an Allosteric Antagonist;98
12.6.4;4.6.4. Relationship Between IC50 and KI for Competitive Antagonists;98
12.6.5;4.6.5. Maximal Inhibition of Binding by an Allosteric Antagonist;98
12.6.6;4.6.6. Relationship Between IC50 and KI for Allosteric Antagonists;98
12.6.7;4.6.7. Two-Stage Binding Reactions;98
12.6.8;4.6.8. Effect of G-protein Coupling on Observed Agonist Affinity;99
12.6.9;4.6.9. Effect of Excess Receptor in Binding Experiments: Saturation Binding Curve;99
12.6.10;4.6.10. Effect of Excess Receptor in Binding Experiments: Displacement Experiments;99
12.7;References;99
13;Chapter 5 : Agonists: The Measurement of Affinity and Efficacy in Functional Assays;102
13.1;5.1. Functional Pharmacological Experiments;102
13.2;5.2. The Choice of Functional Assays;103
13.3;5.3. Recombinant Functional Systems;108
13.4;5.4. Functional Experiments: Dissimulation in Time;109
13.5;5.5. Experiments in Real Time Versus Stop Time;111
13.6;5.6. The Measurement of Agonist Affinity in Functional Experiments;112
13.6.1;5.6.1. Partial Agonists;112
13.6.2;5.6.2. Full Agonists;116
13.7;5.7. Estimates of Relative Efficacy of Agonists in Functional Experiments;117
13.8;5.8. Chapter Summary and Conclusions;118
13.9;5.9. Derivations;119
13.9.1;5.9.1. Relationship Between the EC50 and Affinity of Agonists;119
13.9.2;5.9.2. Method of Barlow, Scott, and Stephenson for Affinity of Partial Agonists;119
13.9.3;5.9.3. Measurement of Agonist Affinity: Method of Furchgott;120
13.9.4;5.9.4. Maximal Response of a Partial Agonist Is Dependent on Efficacy;120
13.10;References;121
14;Chapter 6 : Orthosteric Drug Antagonism;122
14.1;6.1. Introduction;122
14.2;6.2. Kinetics of Drug-Receptor Interaction;123
14.3;6.3. Surmountable Competitive Antagonism;125
14.3.1;6.3.1. Schild Analysis;125
14.3.2;6.3.2. Patterns of Dose-Response Curves That Preclude Schild Analysis;129
14.3.3;6.3.3. Best Practice for the Use of Schild Analysis;130
14.3.4;6.3.4. Analyses for Inverse Agonists in Constitutively Active Receptor Systems;131
14.3.5;6.3.5. Analyses for Partial Agonists;134
14.3.6;6.3.6. The Method of Lew and Angus: Nonlinear Regressional Analysis;135
14.4;6.4. Noncompetitive Antagonism;137
14.5;6.5. Agonist-Antagonist Hemi-Equilibria;140
14.6;6.6. Resultant Analysis;142
14.7;6.7. Chapter Summary and Conclusions;142
14.8;6.8. Derivations;143
14.8.1;6.8.1. Derivation of the Gaddum Equation for Competitive Antagonism;144
14.8.2;6.8.2. Derivation of the Gaddum Equation for Noncompetitive Antagonism;144
14.8.3;6.8.3. Derivation of the Schild Equation;144
14.8.4;6.8.4. Functional Effects of an Inverse Agonist with the Operational Model;145
14.8.5;6.8.5. pA2 Measurement for Inverse Agonists;145
14.8.6;6.8.6. Functional Effects of a Partial Agonist with the Operational Model;145
14.8.7;6.8.7. pA2 Measurements for Partial Agonists;146
14.8.8;6.8.8. Method of Stephenson for Partial Agonist Affinity Measurement;146
14.8.9;6.8.9. Derivation of the Method of Gaddum for Noncompetitive Antagonism;146
14.8.10;6.8.10. Relationship of pA2 and pKB for Insurmountable Orthosteric Antagonism;147
14.8.11;6.8.11. Resultant Analysis;147
14.9;References;148
15;Chapter 7 : Allosteric Drug Antagonism;150
15.1;7.1. Introduction;150
15.2;7.2. The Nature of Receptor Allosterism;150
15.3;7.3. Properties of Allosteric Modulators;152
15.4;7.4. Functional Study of Allosteric Modulators;157
15.4.1;7.4.1. Surmountable Allosteric Modulation (epsiv = 1);158
15.4.2;7.4.2. Insurmountable Allosteric Antagonism (epsiv = 0);159
15.4.3;7.4.3. Variable Effects on Efficacy (epsiv 0);160
15.5;7.5. Measurement of the Potency of Allosteric Insurmountable Antagonists;161
15.6;7.6. Methods for Detecting Allosterism;163
15.7;7.7. Chapter Summary and Conclusions;165
15.8;7.8. Derivations;165
15.8.1;7.8.1. Allosteric Model of Receptor Activity;165
15.8.2;7.8.2. Effects of Allosteric Ligands on Response: Changing Efficacy;166
15.8.3;7.8.3. Schild Analysis for Allosteric Antagonists;166
15.8.4;7.8.4. Relationship of pA2 and pKB for Insurmountable Allosteric Antagonism;167
15.9;References;167
16;Chapter 8 : The Process of Drug Discovery;170
16.1;8.1. Pharmacology in Drug Discovery;170
16.2;8.2. Chemical Sources for Potential Drugs;170
16.3;8.3. Pharmacodynamics and High-Throughput Screening;176
16.4;8.4. Drug Discovery and Development;184
16.4.1;8.4.1. Safety Pharmacology;189
16.5;8.5. Clinical Testing;196
16.6;8.6. Chapter Summary and Conclusions;197
16.7;References;197
17;Chapter 9 : Pharmacokinetics;200
17.1;9.1. Introduction;200
17.2;9.2. Biopharmaceutics;200
17.3;9.3. The Chemistry of "Druglike" Character;201
17.4;9.4. Pharmacokinetics;205
17.4.1;9.4.1. Drug Absorption;205
17.4.2;9.4.2. Route of Drug Administration;209
17.4.3;9.4.3. General Pharmacokinetics;212
17.4.4;9.4.4. Metabolism;214
17.4.5;9.4.5. Clearance;215
17.4.6;9.4.6. Volume of Distribution and Half Life;217
17.4.7;9.4.7. Renal Clearance;223
17.4.8;9.4.8. Bioavailability;225
17.5;9.5. NonLinear Pharmacokinetics;226
17.6;9.6. Multiple Dosing;227
17.7;9.7. Practical Pharmacokinetics;230
17.7.1;9.7.1. Allometric Scaling;230
17.8;9.8. Placement of Pharmacokinetic Assays in Discovery and Development;232
17.9;9.9. Summary and Conclusions;235
17.10;References;235
18;Chapter 10 : Target- and System-Based Strategies for Drug Discovery;236
18.1;10.1. Some Challenges for Modern Drug Discovery;236
18.2;10.2. Target-Based Drug Discovery;237
18.2.1;10.2.1. Target Validation and the Use of Chemical Tools;238
18.2.2;10.2.2. Recombinant Systems;241
18.2.3;10.2.3. Defining Biological Targets;242
18.3;10.3. Systems-Based Drug Discovery;245
18.3.1;10.3.1. Assays in Context;249
18.4;10.4. In Vivo Systems, Biomarkers, and Clinical Feedback;250
18.5;10.5. Types of Therapeutically Active Ligands: Polypharmacology;252
18.6;10.6. Summary and Conclusions;256
18.7;References;257
19;Chapter 11 : "Hit" to Drug: Lead Optimization;260
19.1;11.1. Tracking SAR and Determining Mechanism of Action: Data Driven Drug-Based PharmacoLogy;260
19.2;11.2. Drug Initiation of Response: Agonism;261
19.2.1;11.2.1. Analysis of Full Agonism;262
19.2.2;11.2.2. Quantifying Full Agonist Potency Ratios;264
19.2.3;11.2.3. Analysis of Partial Agonism;264
19.2.4;11.2.4. Fitting Data to the Operational Model;265
19.2.5;11.2.5. Affinity-Dependent versus Efficacy-Dependent Agonist Potency;267
19.2.6;11.2.6. Secondary and Tertiary Testing of Agonists;270
19.3;11.3. Inhibition of Agonist Response: Antagonism;271
19.3.1;11.3.1. Initial Antagonist Potency: pIC50 Curves;271
19.3.2;11.3.2. Secondary Testing of Antagonists;276
19.3.3;11.3.3. Determining Mode of Antagonist Action;278
19.3.4;11.3.4. Use of the pA2 as a Universal Determinant of Antagonist Potency;279
19.3.5;11.3.5. Logistics of Analysis of Antagonism;280
19.4;11.4. Summary and Conclusions;286
19.5;11.5. Derivations;286
19.5.1;11.5.1. System Independence of Full Agonist Potency Ratios: Classical and Operational Models;289
19.5.2;11.5.2. Model for Allosteric Agonism;289
19.5.3;11.5.3. IC50 Correction Factors: Competitive Antagonists;290
19.5.4;11.5.4. Relationship of pA2 and pKB for Insurmountable Orthosteric Antagonism;290
19.5.5;11.5.5. Relationship of pA2 and pKB for Insurmountable Allosteric Antagonism;291
19.5.6;11.5.6. Operational Model for Partial Agonist Interaction with Agonist: Variable Slope;291
19.5.7;11.5.7. Operational Model for Inverse Agonist Interaction with Agonist: Variable Slope;291
19.5.8;11.5.8. Surmountable Allosteric Antagonism: Variable Slope;292
19.5.9;11.5.9. Functional Model for Hemi-Equilibrium Effects: Variable Slope;292
19.5.10;11.5.10. Allosteric Antagonism with Changes in Efficacy: Variable Slope;292
19.5.11;11.5.11. Orthosteric Insurmountable Antagonism: Operational Model with Variable Slope;292
19.5.12;11.5.12. Allosteric Insurmountable Antagonism: Operational Model with Variable Slope;293
19.6;References;293
20;Chapter 12 : Statistics and Experimental Design;294
20.1;12.1. Structure of This Chapter;294
20.2;12.2. Introduction;294
20.3;12.3. Descriptive Statistics: Comparing Sample Data;294
20.3.1;12.3.1. Gaussian Distribution;295
20.3.2;12.3.2. Populations and Samples;295
20.3.3;12.3.3. Confidence Intervals;297
20.3.4;12.3.4. Paired Data Sets;298
20.3.5;12.3.5. One-Way Analysis of Variance;299
20.3.6;12.3.6. Two-Way Analysis of Variance;300
20.3.7;12.3.7. Regression and Correlation;300
20.3.8;12.3.8. Detection of Single versus Multiple Populations;302
20.4;12.4. How Consistent Is Experimental Data with Models?;303
20.4.1;12.4.1. Comparison of Data to Models: Choice of Model;303
20.4.2;12.4.2. Curve Fitting: Good Practice;306
20.4.3;12.4.3. Outliers and Weighting Data Points;306
20.4.4;12.4.4. Overextrapolation of Data;308
20.4.5;12.4.5. Hypothesis Testing: Examples with Dose-Response Curves;310
20.4.6;12.4.6. One Curve or Two? Detection of Differences in Curves;312
20.4.7;12.4.7. Asymmetrical Dose-Response Curves;313
20.4.8;12.4.8. Comparison of Data to Linear Models;314
20.4.9;12.4.9. Is a Given Regression Linear?;315
20.4.10;12.4.10. One or More Regression Lines? Analysis of Covariance;316
20.5;12.5. Comparison of Samples to "Standard Values";318
20.5.1;12.5.1. Comparison of Means by Two Methods or in Two Systems;319
20.5.2;12.5.2. Comparing Assays/Methods with a Range of Ligands;319
20.6;12.6. Experimental Design and Quality Control;320
20.6.1;12.6.1. Detection of Difference in Samples;320
20.6.2;12.6.2. Power Analysis;321
20.7;12.7. Chapter Summary and Conclusions;322
20.8;References;323
21;Chapter 13 : Selected Pharmacological Methods;324
21.1;13.1. Binding Experiments;324
21.1.1;13.1.1. Saturation Binding;324
21.1.2;13.1.2. Displacement Binding;324
21.2;13.2. Functional Assays;326
21.2.1;13.2.1. Determination of Equiactive Concentrations on Dose-Response Curves;326
21.2.2;13.2.2. Method of Barlow, Scott, and Stephenson for Measurement of the Affinity of a Partial Agonist;328
21.2.3;13.2.3. Method of Furchgott for the Measurement of the Affinity of a Full Agonist;329
21.2.4;13.2.4. Schild Analysis for the Measurement of Competitive Antagonist Affinity;331
21.2.5;13.2.5. Method of Stephenson for Measurement of Partial Agonist Affinity;333
21.2.6;13.2.6. Method of Gaddum for Measurement of Noncompetitive Antagonist Affinity;334
21.2.7;13.2.7. Method for Estimating Affinity of Insurmountable Antagonist (Dextral Displacement Observed);336
21.2.8;13.2.8. Resultant Analysis for Measurement of Affinity of Competitive Antagonists with Multiple Properties;337
21.2.9;13.2.9. Measurement of the Affinity and Maximal Allosteric Constant for Allosteric Modulators Producing Surmountable Effects;338
21.2.10;13.2.10. Method for Estimating Affinity of Insurmountable Antagonist (No Dextral Displacement Observed): Detection of Allosteric Effect;339
21.2.11;13.2.11. Measurement of pKB for Competitive Antagonists from a pIC50;341
21.2.12;13.2.12. Kinetics of Antagonist Offset;343
22;Chapter 14 : Exercises in Pharmacodynamics and Pharmacokinetics;348
22.1;14.1. Introduction;348
22.2;14.2. Agonism;348
22.2.1;14.2.1. Agonism: Structure-Activity Relationships;348
22.2.2;14.2.2. Prediction of Agonist Effect;350
22.2.3;14.2.3. "Super Agonists";350
22.2.4;14.2.4. Atypical Agonists;351
22.2.5;14.2.5. Ordering of Affinity and Efficacy in Agonist Series;351
22.2.6;14.2.6. Kinetics of Agonism;351
22.2.7;14.2.7. Affinity-Dominant Versus Efficacy-Dominant Agonists;352
22.2.8;14.2.8. Agonist Affinities and Potencies Do Not Correlate;355
22.2.9;14.2.9. Lack of Agonist Effect;356
22.2.10;14.2.10. Assay-Specific Agonism;357
22.3;14.3. Antagonism;358
22.3.1;14.3.1. Antagonist Potency and Kinetics: Part A;358
22.3.2;14.3.2. Antagonist Potency in pIC50 Format (Kinetics Part B);360
22.3.3;14.3.3. Mechanism of Antagonist Action (Kinetics Part C);361
22.3.4;14.3.4. Mechanism of Antagonist Action: Curve Patterns;362
22.3.5;14.3.5. Mechanism of Action: Incomplete Antagonism;362
22.3.6;14.3.6. pIC50 Mode: Antagonism Below Basal;364
22.3.7;14.3.7. Secondary Effects of Antagonists;365
22.3.8;14.3.8. Antagonist Potency Variably Dependent on Agonist Concentration;365
22.4;14.4. In Vitro-In Vivo Transitions and General Discovery;367
22.4.1;14.4.1. "Silent Antagonism";367
22.4.2;14.4.2. Loss of Activity;368
22.4.3;14.4.3. Marking Relevant Agonism;369
22.4.4;14.4.4. In Vitro-In Vivo Correspondence of Activity;369
22.4.5;14.4.5. Divergent Agonist-Dependent Antagonism;370
22.5;14.5. SAR Exercises;372
22.5.1;14.5.1. Surrogate Screens;372
22.6;14.6. Pharmacokinetics;372
22.6.1;14.6.1. Clearance;372
22.6.2;14.6.2. Drug-Drug Interactions;373
22.6.3;14.6.3. Distribution I;373
22.6.4;14.6.4. Distribution II;373
22.6.5;14.6.5. Half Life I;374
22.6.6;14.6.6. Half Life II;374
22.6.7;14.6.7. Half Life III;375
22.6.8;14.6.8. Renal Clearance I;375
22.6.9;14.6.9. Renal Clearance II;375
22.6.10;14.6.10. Renal Clearance III;375
22.6.11;14.6.11. Absorption;375
22.6.12;14.6.12. Predictive Pharmacokinetics I;375
22.6.13;14.6.13. Predictive Pharmacokinetics II;376
22.6.14;14.6.14. Predictive Pharmacokinetics III;376
22.6.15;14.6.15. Log D and Pharmacokinetics;376
22.7;14.7. Conclusions;376
22.8;References;376
23;Appendices;378
23.1;A.1. Statistical Tables of Use for Assessing Significant Difference;378
23.1.1;A.1.1. t-Distribution;378
23.1.2;A.1.2. F-Distribution;379
23.2;A.2. Mathematical Fitting Functions;386
24;Glossary of Pharmacological Terms;392
25;Index;400