Title Page Copyright page Preface About the Book Emboldened key words Boxes Key points Struggle Alert Questions Further reading Appendix and glossary Links Disclaimer About Oxford Learning Link Student resources Multiple choice questions Rotatable 3D structures Web articles Molecular modelling Protein Data Bank Lecturer resources Test Bank Answers Figures from the book PowerPoint slides Acknowledgements Table of Contents List of Boxes General interest Synthesis Clinical correlation Acronyms and abbreviations 1 Drugs and drug targets: an overview 1.1 What is a drug? 1.2 Drug targets 1.2.1 Cell structure 1.2.2 Drug targets at the molecular level 1.3 Intermolecular bonding forces 1.3.1 Electrostatic or ionic bonds 1.3.2 Hydrogen bonds 1.3.2.1 Conventional hydrogen bonds 1.3.2.2 Unconventional hydrogen bonds 1.3.3 Van der Waals interactions 1.3.4 Dipole–dipole, ion–dipole, and cation–π interactions 1.3.5 π–π interactions 1.3.6 Halogen bonds 1.3.7 Repulsive interactions 1.3.8 The role of water and hydrophobic interactions 1.4 Pharmacokinetic issues and medicines 1.5 Classification of drugs 1.5.1 By pharmacological effect 1.5.2 By chemical structure 1.5.3 By target system 1.5.4 By target molecule 1.6 Naming of drugs and medicines Questions Further Reading Websites List of Key Terms Part A Drug targets: Structure and function 2 Protein structure and function 2.1 The primary structure of proteins 2.2 The secondary structure of proteins 2.2.1 The α-helix 2.2.2 The β-pleated sheet 2.2.3 The β-turn 2.3 The tertiary structure of proteins 2.3.1 Covalent bonds: disulphide links 2.3.2 Ionic or electrostatic bonds 2.3.3 Hydrogen bonds 2.3.4 Van der Waals and hydrophobic interactions 2.3.5 Relative importance of bonding interactions 2.3.6 Role of the planar peptide bond 2.4 The quaternary structure of proteins 2.5 Translation and post-translational modifications 2.6 Proteomics 2.7 Protein function 2.7.1 Structural proteins 2.7.2 Transport proteins 2.7.3 Enzymes and receptors 2.7.4 Miscellaneous proteins and protein–protein interactions Questions Oxford Learning Link Further Reading List of Key Terms 3 Enzymes: structure and function 3.1 Enzymes as catalysts 3.2 How do enzymes catalyse reactions? 3.3 The active site of an enzyme 3.4 Substrate binding at an active site 3.5 The catalytic role of enzymes 3.5.1 Binding interactions 3.5.2 Acid/base catalysis 3.5.3 Nucleophilic groups 3.5.4 Stabilization of the transition state 3.5.5 Cofactors 3.5.6 Naming and classification of enzymes 3.5.7 Genetic polymorphism and enzymes 3.6 Regulation of enzymes 3.7 Isozymes 3.8 Enzyme kinetics 3.8.1 The Michaelis–Menten equation 3.8.2 Lineweaver–Burk plots Questions Further Reading List of Key Terms 4 Receptors: structure and function 4.1 Role of the receptor 4.2 Neurotransmitters and hormones 4.3 Receptor types and subtypes 4.4 Receptor activation 4.5 How does the binding site change shape? 4.6 Ion channel receptors 4.6.1 General principles 4.6.2 Structure 4.6.3 Gating 4.6.4 Ligand-gated and voltage-gated ion channels 4.7 G-Protein-coupled receptors 4.7.1 General principles 4.7.2 Structure of G-protein-coupled receptors 4.7.3 The rhodopsin-like family of G-protein-coupled receptors 4.7.4 Dimerization of G-coupled receptors 4.8 Kinase receptors 4.8.1 General principles 4.8.2 Structure of tyrosine kinase receptors 4.8.3 Activation mechanism for tyrosine kinase receptors 4.8.4 Tyrosine kinase receptors as targets in drug discovery 4.8.4.1 The ErbB family of tyrosine kinase receptors 4.8.4.2 Vascular endothelial growth factor receptors 4.8.4.3 Platelet-derived growth factor receptors 4.8.4.4 Stem cell growth factor receptors 4.8.4.5 Anaplastic lymphoma kinase 4.8.4.6 The RET receptor 4.8.4.7 Hepatocyte growth factor receptor or c-MET receptor 4.9 Intracellular receptors 4.10 Regulation of receptor activity 4.11 Genetic polymorphism and receptors Questions Further Reading List of Key Terms 5 Receptors and signal transduction 5.1 Signal transduction pathways for G-protein-coupled receptors (GPCRs) 5.1.1 Interaction of the receptor–ligand complex with G-proteins 5.1.2 Signal transduction pathways involving the α-subunit 5.2 Signal transduction involving G-proteins and adenylate cyclase 5.2.1 Activation of adenylate cyclase by the αs-subunit 5.2.2 Activation of protein kinase A 5.2.3 The Gi-protein 5.2.4 General points about the signalling cascade involving cyclic AMP 5.2.5 The role of the βγ-dimer 5.2.6 Phosphorylation 5.3 Signal transduction involving G-proteins and phospholipase Cβ 5.3.1 G-protein effect on phospholipase Cβ 5.3.2 Action of the secondary messenger: diacylglycerol 5.3.3 Action of the secondary messenger: inositol triphosphate 5.3.4 Resynthesis of phosphatidylinositol diphosphate 5.4 The role of β-arrestins in modulating the activity of G-protein-coupled receptors 5.5 Signal transduction involving kinase receptors 5.5.1 Activation of signalling proteins and enzymes 5.5.2 The MAPK signal transduction pathway 5.5.3 Activation of guanylate cyclase by kinase receptors 5.5.4 The JAK-STAT signal transduction pathway 5.5.5 The PI3K/Akt/mTOR signal transduction pathway 5.6 The hedgehog signalling pathway Questions Further Reading List of Key Terms 6 Nucleic acids: structure and function 6.1 Structure of DNA 6.1.1 The primary structure of DNA 6.1.2 The secondary structure of DNA 6.1.3 The tertiary structure of DNA 6.1.4 Chromatins 6.1.5 Genetic polymorphism and personalized medicine 6.2 Ribonucleic acid and protein synthesis 6.2.1 Structure of RNA 6.2.2 Transcription and translation 6.2.3 Small nuclear RNA 6.2.4 The regulatory role of RNA 6.3 Genetic illnesses 6.4 Molecular biology and genetic engineering Questions Further Reading List of Key Terms Part B Pharmacodynamics and pharmacokinetics 7 Enzymes as drug targets 7.1 Inhibitors acting at the active site of an enzyme 7.1.1 Reversible inhibitors 7.1.2 Irreversible inhibitors 7.2 Inhibitors acting at allosteric binding sites 7.3 Uncompetitive and non-competitive inhibitors 7.4 Transition-state analogues: renin inhibitors 7.5 Suicide substrates 7.6 Isozyme selectivity of inhibitors 7.7 Medicinal uses of enzyme inhibitors 7.7.1 Enzyme inhibitors used against microorganisms 7.7.2 Enzyme inhibitors used against viruses 7.7.3 Enzyme inhibitors used against the body’s own enzymes 7.7.4 Enzyme modulators 7.8 Enzyme kinetics 7.8.1 Lineweaver–Burk plots 7.8.2 Comparison of inhibitors Questions Further Reading List of Key Terms 8 Receptors as drug targets 8.1 Introduction 8.2 The design of agonists 8.2.1 Binding groups 8.2.2 Position of the binding groups 8.2.3 Size and shape 8.2.4 Other design strategies 8.2.5 Pharmacodynamics and pharmacokinetics 8.2.6 Examples of agonists 8.2.7 Allosteric modulators 8.3 The design of antagonists 8.3.1 Antagonists acting at the binding site 8.3.2 Antagonists acting outside the binding site 8.4 Partial agonists 8.5 Inverse agonists 8.6 Desensitization and sensitization 8.7 Tolerance and dependence 8.8 Receptor types and subtypes 8.9 Affinity, efficacy, and potency Questions Further Reading List of Key Terms 9 Nucleic acids as drug targets 9.1 Intercalating drugs acting on DNA 9.2 Topoisomerase poisons: non-intercalating 9.3 Alkylating and metallating agents 9.3.1 Nitrogen mustards 9.3.2 Nitrosoureas 9.3.3 Busulfan 9.3.4 Cisplatin 9.3.5 Dacarbazine and procarbazine 9.3.6 Mitomycin C 9.4 Chain cutters 9.5 Chain terminators 9.6 Control of gene transcription 9.7 Agents that act on RNA 9.7.1 Agents that bind to ribosomes 9.7.2 Antisense therapy Questions Further Reading List of Key Terms 10 Miscellaneous drug targets 10.1 Transport proteins as drug targets 10.2 Structural proteins as drug targets 10.2.1 Viral structural proteins as drug targets 10.2.2 Tubulin as a drug target 10.2.2.1 Agents that inhibit tubulin polymerization 10.2.2.2 Agents that inhibit tubulin depolymerization 10.3 Biosynthetic building blocks as drug targets 10.4 Biosynthetic processes as drug targets: chain terminators 10.5 Protein–protein interactions 10.5.1 Inhibition of protein–protein interactions 10.5.2 Promotion of protein–protein interactions 10.6 Lipids as a drug target 10.6.1 ‘Tunnelling molecules’ 10.6.2 Ion carriers 10.6.3 Tethers and anchors 10.7 Carbohydrates as drug targets 10.7.1 Glycomics 10.7.2 Antigens and antibodies 10.7.3 Cyclodextrins Questions Further Reading List of Key Terms 11 Pharmacokinetics and related topics 11.1 The three phases of drug action 11.2 A typical journey for an orally active drug 11.3 Drug absorption 11.4 Drug distribution 11.4.1 Distribution round the blood supply 11.4.2 Distribution to tissues 11.4.3 Distribution to cells 11.4.4 Other distribution factors 11.4.5 Blood–brain barrier 11.4.6 Placental barrier 11.4.7 Drug–drug interactions 11.5 Drug metabolism 11.5.1 Phase I and phase II metabolism 11.5.2 Phase I transformations catalysed by cytochrome P450 enzymes 11.5.3 Phase I transformations catalysed by flavin-containing monooxygenases 11.5.4 Phase I transformations catalysed by other enzymes 11.5.5 Phase II transformations 11.5.6 Metabolic stability 11.5.7 The first pass effect 11.6 Drug excretion 11.7 Drug administration 11.7.1 Oral administration 11.7.2 Absorption through mucous membranes 11.7.3 Rectal administration 11.7.4 Topical administration 11.7.5 Inhalation 11.7.6 Injection 11.7.7 Implants 11.8 Drug dosing 11.8.1 Drug half-life 11.8.2 Steady state concentration 11.8.3 Drug tolerance 11.8.4 Bioavailability 11.9 Formulation 11.10 Drug delivery Questions Further Reading List of Key Terms Case study 1 Statins CS1.1 Cholesterol and coronary heart disease CS1.2 The target enzyme CS1.3 The discovery of statins CS1.3.1 Type I statins CS1.3.2 Type II statins CS1.4 Mechanism of action for statins—pharmacodynamics CS1.5 Binding interactions of statins CS1.6 Other mechanisms of action for statins CS1.7 Other targets for cholesterol-lowering drugs Further Reading Part C Drug discovery, design, and development 12 Drug discovery: finding a lead 12.1 Choosing a disease 12.2 Choosing a drug target 12.2.1 Drug targets 12.2.2 Discovering drug targets 12.2.3 Target specificity and selectivity between species 12.2.4 Target specificity and selectivity within the body 12.2.5 Targeting drugs to specific organs and tissues 12.2.6 Pitfalls 12.2.7 Multi-target drugs 12.3 Identifying a bioassay 12.3.1 Choice of bioassay 12.3.2 In vitro tests 12.3.3 In vivo tests 12.3.4 Test validity 12.3.5 High-throughput screening 12.3.6 Screening by NMR 12.3.7 Affinity screening 12.3.8 Surface plasmon resonance 12.3.9 Scintillation proximity assay 12.3.10 Isothermal titration calorimetry 12.3.11 Virtual screening 12.4 Finding a lead compound 12.4.1 Screening of natural products 12.4.1.1 The plant kingdom 12.4.1.2 Microorganisms 12.4.1.3 Marine sources 12.4.1.4 Animal sources 12.4.1.5 Venoms and toxins 12.4.2 Medical folklore 12.4.3 Screening synthetic compound ‘libraries’ 12.4.4 Existing drugs 12.4.4.1 ‘Me too’ and ‘me better’ drugs 12.4.4.2 Enhancing a side effect 12.4.5 Starting from the natural ligand or modulator 12.4.5.1 Natural ligands for receptors 12.4.5.2 Natural substrates for enzymes 12.4.5.3 Enzyme products as lead compounds 12.4.5.4 Natural modulators as lead compounds 12.4.6 Combinatorial and parallel synthesis 12.4.7 Computer-aided design of lead compounds 12.4.8 Serendipity and the prepared mind 12.4.9 Computerized searching of structural databases 12.4.10 Fragment-based lead discovery 12.4.11 Properties of lead compounds 12.5 Isolation and purification 12.6 Structure determination 12.7 Herbal medicine Questions Further Reading List of Key Terms 13 Drug design: optimizing target interactions 13.1 Structure–activity relationships 13.1.1 Binding role of alcohols and phenols 13.1.2 Binding role of aromatic rings 13.1.3 Binding role of alkenes 13.1.4 Binding role of ketones and aldehydes 13.1.5 Binding role of amines 13.1.6 Binding role of amides 13.1.7 Binding role of quaternary ammonium salts 13.1.8 Binding role of carboxylic acids 13.1.9 Binding role of esters 13.1.10 Binding role of alkyl and aryl halides 13.1.11 Binding role of thiols and ethers 13.1.12 Binding role of phosphates, phosphonates, and phosphinates 13.1.13 Binding role of other functional groups 13.1.14 Binding role of alkyl groups and the carbon skeleton 13.1.15 Binding role of heterocycles 13.1.16 Isosteres 13.1.17 Testing procedures 13.1.18 SAR in drug optimization 13.2 Identification of a pharmacophore 13.3 Drug optimization: strategies in drug design 13.3.1 Variation of substituents 13.3.1.1 Alkyl substituents 13.3.1.2 Substituents on aromatic or heteroaromatic rings 13.3.1.3 Varying substituents to change the pKa of ionizable groups 13.3.1.4 Synergistic effects 13.3.2 Extension of the structure 13.3.3 Chain extension/contraction 13.3.4 Ring expansion/contraction 13.3.5 Ring variations 13.3.6 Ring fusions 13.3.7 Isosteres and bio-isosteres 13.3.8 Simplification of the structure 13.3.9 Rigidification of the structure 13.3.10 Conformational blockers 13.3.11 Rigidification through intramolecular bonds 13.3.12 Structure-based drug design and molecular modelling 13.3.13 Drug design by NMR spectroscopy 13.3.14 The elements of luck and inspiration 13.3.15 Designing drugs to interact with more than one target 13.3.15.1 Agents designed from known drugs 13.3.15.2 Agents designed from non-selective lead compounds 13.4 Selectivity 13.5 Pharmacokinetics Questions Further Reading List of Key Terms 14 Drug design: optimizing access to the target 14.1 Optimizing hydrophilic/hydrophobic properties 14.1.1 Masking polar functional groups to decrease polarity 14.1.2 Adding or removing polar functional groups to vary polarity 14.1.3 Varying hydrophobic substituents to vary polarity 14.1.4 Variation of N-alkyl substituents to vary pKa 14.1.5 Other structural variations affecting pKa 14.1.6 Bio-isosteres for polar groups involved in binding interactions 14.2 Making drugs more resistant to chemical and enzymatic degradation 14.2.1 Steric shields 14.2.2 Electronic effects of bio-isosteres and substituents 14.2.3 Steric and electronic modifications 14.2.4 Metabolic blockers 14.2.5 Removal or replacement of susceptible metabolic groups 14.2.6 Group shifts 14.2.7 Ring variation and ring substituents 14.3 Making drugs less resistant to drug metabolism 14.3.1 Introducing metabolically susceptible groups 14.3.2 Self-destruct drugs 14.4 Targeting drugs 14.4.1 Targeting tumour cells: ‘search and destroy’ drugs 14.4.2 Targeting gastrointestinal infections 14.4.3 Targeting peripheral regions rather than the central nervous system 14.4.4 Targeting with membrane tethers 14.4.5 Targeting antibacterial agents using siderophores 14.5 Reducing toxicity 14.6 Prodrugs 14.6.1 Prodrugs to improve membrane permeability 14.6.1.1 Esters as prodrugs 14.6.1.2 N-Methylated prodrugs 14.6.1.3 Trojan horse approach for transport proteins 14.6.2 Prodrugs to prolong drug activity 14.6.3 Prodrugs masking drug toxicity and side effects 14.6.4 Prodrugs to lower water solubility 14.6.5 Prodrugs to improve water solubility 14.6.6 Prodrugs used in the targeting of drugs 14.6.7 Prodrugs to increase chemical stability 14.6.8 Prodrugs activated by external influence (sleeping agents) 14.7 Drug alliances 14.7.1 ‘Sentry’ drugs 14.7.2 Localizing a drug’s area of activity 14.7.3 Increasing absorption 14.8 Endogenous compounds as drugs 14.8.1 Neurotransmitters 14.8.2 Natural hormones, peptides, and proteins as drugs 14.9 Peptides and peptidomimetics in drug design 14.9.1 Peptidomimetics 14.9.2 Peptide drugs 14.10 Oligonucleotides as drugs Questions Further Reading List of Key Terms 15 Getting the drug to market 15.1 Preclinical and clinical trials 15.1.1 Toxicity testing 15.1.2 Drug metabolism studies 15.1.3 Pharmacology, formulation, and stability tests 15.1.4 Clinical trials 15.1.4.1 Phase I studies 15.1.4.2 Phase II studies 15.1.4.3 Phase III studies 15.1.4.4 Phase IV studies 15.1.4.5 Ethical issues 15.2 Patenting and regulatory affairs 15.2.1 Patents 15.2.2 Regulatory affairs 15.2.2.1 The regulatory process 15.2.2.2 Fast-tracking and orphan drugs 15.2.2.3 Good laboratory, manufacturing, and clinical practice 15.2.2.4 Cost-versus-benefit analysis 15.3 Chemical and process development 15.3.1 Chemical development 15.3.2 Process development 15.3.3 Choice of drug candidate 15.3.4 Natural products Questions Further Reading List of Key Terms Case study 2 The design of ACE inhibitors Further Reading Case study 3 Artemisinin and related antimalarial drugs CS3.1 Introduction CS3.2 Artemisinin CS3.3 Structure and synthesis of artemisinin CS3.4 Structure–activity relationships CS3.5 Mechanism of action CS3.6 Drug design and development Further Reading List of Key Terms Case study 4 The design of oxamniquine CS4.1 Introduction CS4.2 From lucanthone to oxamniquine CS 4.3 Mechanism of action CS4.4 Other agents Further Reading Case study 5 Fosmidomycin as an antimalarial agent CS5.1 Introduction CS5.2 The malarial parasite CS5.3 The target for fosmidomycin: DOXP reductoisomerase CS5.4 Fosmidomycin as a transition-state analogue CS5.5 Binding interactions of fosmidomycin CS5.6 Structure–activity relationships (SARs) CS5.7 Properties of fosmidomycin CS5.8 Analogues of fosmidomycin via an extension strategy CS5.9 Prodrugs of fosmidomycin Further Reading Part D Tools of the trade 16 Combinatorial and parallel synthesis 16.1 Combinatorial and parallel synthesis in medicinal chemistry projects 16.2 Solid-phase techniques 16.2.1 The solid support 16.2.2 The anchor/linker 16.2.3 Examples of solid-phase syntheses 16.3 Planning and designing a compound library 16.3.1 ‘Spider-like’ scaffolds 16.3.2 Designing ‘drug-like’ molecules 16.3.3 Synthesis of scaffolds 16.3.4 Substituent variation 16.3.5 Designing compound libraries for lead optimization 16.3.6 Computer-designed libraries 16.4 Testing for activity 16.4.1 High-throughput screening 16.4.2 Screening ‘on bead’ or ‘off bead’ 16.5 Parallel synthesis 16.5.1 Solid-phase extraction 16.5.2 The use of resins in solution phase organic synthesis (SPOS) 16.5.3 Reagents attached to solid support: catch and release 16.5.4 Microwave technology 16.5.5 Microfluidics in parallel synthesis 16.6 Combinatorial synthesis 16.6.1 The mix and split method in combinatorial synthesis 16.6.2 Structure determination of the active compound(s) 16.6.2.1 Tagging 16.6.2.2 Photolithography 16.6.3 Dynamic combinatorial synthesis Questions Further Reading List of Key Terms 17 In silico drug design 17.1 Molecular and quantum mechanics 17.1.1 Molecular mechanics 17.1.2 Quantum mechanics 17.1.3 Choice of method 17.2 Drawing chemical structures 17.3 3D structures 17.4 Energy minimization 17.5 Viewing 3D molecules 17.6 Molecular dimensions 17.7 Molecular properties 17.7.1 Partial charges 17.7.2 Molecular electrostatic potentials 17.7.3 Molecular orbitals 17.7.4 Spectroscopic transitions 17.7.5 The use of grids in measuring molecular properties 17.8 Conformational analysis 17.8.1 Local and global energy minima 17.8.2 Molecular dynamics 17.8.3 Stepwise bond rotation 17.8.4 Monte Carlo and the Metropolis method 17.8.5 Genetic and evolutionary algorithms 17.9 Structure comparisons and overlays 17.10 Identifying the active conformation 17.10.1 X-ray crystallography 17.10.2 Comparison of rigid and non-rigid ligands 17.11 3D pharmacophore identification 17.11.1 X-ray crystallography 17.11.2 Structural comparison of active compounds 17.11.3 Automatic identification of pharmacophores 17.12 Docking procedures 17.12.1 Manual docking 17.12.2 Automatic docking 17.12.3 Defining the molecular surface of a binding site 17.12.4 Rigid docking by shape complementarity 17.12.5 The use of grids in docking programs 17.12.6 Rigid docking by matching hydrogen-bonding groups 17.12.7 Rigid docking of flexible ligands: the FLOG program 17.12.8 Docking of flexible ligands: anchor and grow programs 17.12.8.1 Directed Dock and Dock 4.0 17.12.8.2 FlexX 17.12.8.3 The Hammerhead program 17.12.9 Docking of flexible ligands: simulated annealing and genetic algorithms 17.13 Automated screening of databases for lead compounds and drug design 17.14 Protein mapping 17.14.1 Constructing a model protein: homology modelling 17.14.2 Constructing a binding site: hypothetical pseudoreceptors 17.15 De novo drug design 17.15.1 General principles of de novo drug design 17.15.2 Automated de novo drug design 17.15.2.1 LUDI Stage 1: Identification of interaction sites Stage 2: Fitting molecular fragments Stage 3: Fragment bridging 17.15.2.2 SPROUT 17.15.2.3 LEGEND 17.15.2.4 GROW, ALLEGROW, and SYNOPSIS 17.16 Planning compound libraries 17.17 Database handling Questions Further Reading List of Key Terms 18 Quantitative structure–activity relationships (QSAR) 18.1 Graphs and equations 18.2 Physicochemical properties 18.2.1 Hydrophobicity 18.2.1.1 The partition coefficient (P) 18.2.1.2 The substituent hydrophobicity constant (π) 18.2.1.3 P versus π 18.2.2 Electronic effects 18.2.3 Steric factors 18.2.3.1 Taft’s steric factor (Es) 18.2.3.2 Molar refractivity 18.2.3.3 Verloop steric parameter 18.2.4 Other physicochemical parameters 18.3 Hansch equation 18.4 The Craig plot 18.5 The Topliss scheme 18.6 Bio-isosteres 18.7 The Free–Wilson approach 18.8 Planning a QSAR study 18.9 Case study: anti-allergic activity of a series of pyranenamines 18.10 3D QSAR 18.10.1 Defining steric and electrostatic fields 18.10.2 Relating shape and electronic distribution to biological activity 18.10.3 Advantages of CoMFA over traditional QSAR 18.10.4 Potential problems of CoMFA 18.10.5 Other 3D QSAR methods 18.10.6 Case study: inhibitors of tubulin polymerization Questions Further Reading List of Key Terms Case study 6 Design of a thymidylate synthase inhibitor Further Reading List of Key Terms Part E Selected topics in medicinal chemistry 19 Antibacterial agents 19.1 History of antibacterial agents 19.2 The bacterial cell 19.3 Mechanisms of antibacterial action 19.4 Antibacterial agents that act against cell metabolism (antimetabolites) 19.4.1 Sulphonamides 19.4.1.1 The history of sulphonamides 19.4.1.2 Structure–activity relationships 19.4.1.3 Sulphanilamide analogues 19.4.1.4 Applications of sulphonamides 19.4.1.5 Mechanism of action 19.4.2 Examples of other antimetabolites 19.4.2.1 Trimethoprim 19.4.2.2 Sulphones 19.5 Antibacterial agents that inhibit cell wall synthesis 19.5.1 Penicillins 19.5.1.1 History of penicillins 19.5.1.2 Structure of benzylpenicillin and phenoxymethylpenicillin 19.5.1.3 Properties of benzylpenicillin 19.5.1.4 Mechanism of action for penicillin Structure of the cell wall The transpeptidase enzyme and its inhibition 19.5.1.5 Resistance to penicillin Physical barriers Presence of β-lactamase enzymes High levels of transpeptidase enzyme produced Affinity of the transpeptidase enzyme to penicillin Transport back across the outer membrane of Gram-negative bacteria Mutations and genetic transfers 19.5.1.6 Methods of synthesizing penicillin analogues Fermentation Semi-synthetic procedure 19.5.1.7 Structure–activity relationships of penicillins 19.5.1.8 Penicillin analogues Acid sensitivity of penicillins Acid-resistant penicillins β-Lactamase-resistant penicillins Broad-spectrum penicillins Broad-spectrum penicillins: the aminopenicillins Broad-spectrum penicillins: the carboxypenicillins Broad-spectrum penicillins: the ureidopenicillins 19.5.1.9 Synergism of penicillins with other drugs 19.5.2 Cephalosporins 19.5.2.1 Cephalosporin C Discovery and structure of cephalosporin C Properties of cephalosporin C Structure–activity relationships of cephalosporin C 19.5.2.2 Synthesis of cephalosporin analogues at position 7 19.5.2.3 First-generation cephalosporins 19.5.2.4 Second-generation cephalosporins Cephamycins Oximinocephalosporins 19.5.2.5 Third-generation cephalosporins 19.5.2.6 Fourth-generation cephalosporins 19.5.2.7 Fifth-generation cephalosporins 19.5.2.8 Resistance to cephalosporins 19.5.3 Other β-lactam antibiotics 19.5.3.1 Carbapenems 19.5.3.2 Monobactams 19.5.4 β-Lactamase inhibitors 19.5.4.1 Clavulanic acid 19.5.4.2 Penicillanic acid sulphone derivatives 19.5.4.3 Olivanic acids 19.5.4.4 β-Lactamase inhibitors lacking a β-lactam ring 19.5.5 Other drugs that act on bacterial cell wall biosynthesis 19.5.5.1 d-Cycloserine and bacitracin 19.5.5.2 The glycopeptides: vancomycin and vancomycin analogues 19.6 Antibacterial agents that act on the plasma membrane structure 19.6.1 Valinomycin and gramicidin A 19.6.2 Polymyxin B 19.6.3 Killer nanotubes 19.6.4 Cyclic lipopeptides 19.7 Antibacterial agents that impair protein synthesis: translation 19.7.1 Aminoglycosides 19.7.2 Tetracyclines 19.7.3 Chloramphenicol 19.7.4 Macrolides 19.7.5 Lincosamides 19.7.6 Streptogramins 19.7.7 Oxazolidinones 19.7.8 Pleuromutilins 19.8 Agents that act on nucleic acid transcription and replication 19.8.1 Quinolones and fluoroquinolones 19.8.2 Spiropyrimidinetriones 19.8.3 Aminoacridines 19.8.4 Rifamycins 19.8.5 Nitroimidazoles and nitrofurantoin 19.8.6 Inhibitors of bacterial RNA polymerase 19.9 Miscellaneous agents 19.10 Antibodies 19.11 Drug resistance 19.11.1 Drug resistance by mutation 19.11.2 Drug resistance by genetic transfer 19.11.3 Other factors affecting drug resistance 19.11.4 The way ahead Questions Further Reading List of Key Terms 20 Antiviral agents 20.1 Viruses and viral diseases 20.2 Structure of viruses 20.3 Life cycle of viruses 20.4 Vaccination 20.5 Antiviral drugs: general principles 20.6 Antiviral drugs used against DNA viruses 20.6.1 Inhibitors of viral DNA polymerase 20.6.2 Inhibitors of the DNA terminase complex 20.6.3 Kinase inhibitors 20.6.4 Inhibitors of tubulin polymerization 20.6.5 Antisense therapy 20.6.6 Antiviral drugs acting against hepatitis B 20.7 Antiviral drugs acting against RNA viruses: the human immunodeficiency virus (HIV) 20.7.1 Structure and life cycle of HIV 20.7.2 Antiviral therapy against HIV 20.7.3 Inhibitors of viral reverse transcriptase 20.7.3.1 Nucleoside reverse transcriptase inhibitors 20.7.3.2 Non-nucleoside reverse transcriptase inhibitors 20.7.4 Protease inhibitors 20.7.4.1 The HIV protease enzyme 20.7.4.2 Design of HIV protease inhibitors 20.7.4.3 Saquinavir 20.7.4.4 Ritonavir and lopinavir 20.7.4.5 Indinavir 20.7.4.6 Nelfinavir 20.7.4.7 Palinavir 20.7.4.8 Amprenavir and darunavir 20.7.4.9 Atazanavir 20.7.4.10 Tipranavir 20.7.4.11 Alternative design strategies for antiviral drugs targeting the HIV protease enzyme 20.7.5 Integrase inhibitors 20.7.6 Cell entry inhibitors 20.7.6.1 Fusion inhibitors targeting the viral gp41 glycoprotein 20.7.6.2 Inhibitors of the viral glycoprotein gp120 20.7.6.3 Inhibitors of the host cell CD4 protein 20.7.6.4 Inhibitors of the host cell CCR5 chemokine receptor 20.8 Antiviral drugs acting against RNA viruses: flu virus 20.8.1 Structure and life cycle of the influenza virus 20.8.2 Ion channel disrupters: adamantanes 20.8.3 Neuraminidase inhibitors 20.8.3.1 Structure and mechanism of neuraminidase 20.8.3.2 Transition-state inhibitors: development of zanamivir (Relenza™) 20.8.3.3 Transition-state inhibitors: 6-carboxamides 20.8.3.4 Carbocyclic analogues: development of oseltamivir (Tamiflu™) 20.8.3.5 Other ring systems 20.8.3.6 Resistance studies 20.8.4 Cap-dependent endonuclease inhibitors 20.9 Antiviral drugs acting against RNA viruses: cold virus 20.10 Antiviral drugs acting against RNA viruses: hepatitis C 20.10.1 Inhibitors of HCV NS3-4A protease 20.10.1.1 Introduction 20.10.1.2 Design of boceprevir and telaprevir 20.10.1.3 Second-generation protease inhibitors 20.10.2 Inhibitors of HCV NS5B RNA-dependent RNA polymerase 20.10.3 Inhibitors of HCV NS5A protein 20.10.3.1 Symmetrical inhibitors 20.10.3.2 Unsymmetrical inhibitors 20.10.4 Other targets 20.11 Broad-spectrum antiviral agents 20.11.1 Agents acting against cytidine triphosphate synthetase 20.11.2 Agents acting against S-adenosylhomocysteine hydrolase 20.11.3 Ribavirin 20.11.4 Interferons 20.11.5 Antibodies and ribozymes 20.11.5.1 Antibodies 20.11.5.2 Ribozymes 20.12 Bioterrorism and smallpox Questions Further Reading List of Key Terms 21 Anticancer agents 21.1 Cancer: an introduction 21.1.1 Definitions 21.1.2 Causes of cancer 21.1.3 Genetic faults leading to cancer: proto-oncogenes and oncogenes 21.1.3.1 Activation of proto-oncogenes 21.1.3.2 Inactivation of tumour suppression genes (anti-oncogenes) 21.1.3.3 The consequences of genetic defects 21.1.4 Abnormal signalling pathways 21.1.5 Insensitivity to growth-inhibitory signals 21.1.6 Abnormalities in cell cycle regulation 21.1.7 Apoptosis and the p53 protein 21.1.8 Telomeres 21.1.9 Angiogenesis 21.1.10 Tissue invasion and metastasis 21.1.11 Treatment of cancer 21.1.12 Resistance 21.2 Drugs acting directly on nucleic acids 21.2.1 Intercalating agents 21.2.2 Non-intercalating agents that inhibit the action of topoisomerase enzymes on DNA 21.2.2.1 Podophyllotoxins 21.2.2.2 Camptothecins 21.2.3 Alkylating and metallating agents 21.2.3.1 Nitrogen mustards 21.2.3.2 Cisplatin and cisplatin analogues: metallating agents 21.2.3.3 CC 1065 analogues 21.2.3.4 Ecteinascidins 21.2.3.5 Other alkylating agents 21.2.4 Chain cutters 21.3 Drugs acting on enzymes: antimetabolites 21.3.1 Dihydrofolate reductase inhibitors 21.3.2 Inhibitors of thymidylate synthase 21.3.3 Inhibitors of ribonucleotide reductase 21.3.4 Inhibitors of adenosine deaminase 21.3.5 Cytidine deaminase inhibitors 21.3.6 Inhibitors of DNA polymerases 21.3.7 Purine antagonists 21.3.8 DNA methyltransferase inhibitors 21.4 Hormone-based therapies 21.4.1 Glucocorticoids, estrogens, progestins, and androgens 21.4.2 Luteinizing hormone-releasing hormone receptor agonists and antagonists 21.4.3 Anti-estrogens 21.4.4 Anti-androgens 21.4.5 Aromatase inhibitors 21.4.6 Mitotane 21.4.7 Somatostatin receptor agonists 21.5 Drugs acting on structural proteins 21.5.1 Agents that inhibit tubulin polymerization 21.5.2 Agents that inhibit tubulin depolymerization 21.6 Inhibitors of signalling pathways 21.6.1 Inhibition of farnesyl trans

Malcolm Hardy...[et Al ]. Bibliography:p. 217-225.-includes Index.

本书集合了国内众多学者的研究成果,他们分别从法律,经济,社会等不同学科出发,对中国互联网的发展演变进行跨界观察.这里既有对个别互联网案例的分析与解读,也有对信息社会中新格局,新秩序的宏观探索;既引入了互联网的前沿研究方法,也体现了对新社会形态的争锋思辨

Stephen Kumalo is a Reverend of a St Mark's Church in a small remote village Ndotsheni of eastern South Africa. He lives alone and very poor live together with his wife. Most of his relatives as sister, brother and even son gone to Johannesburg by different reasons and never came back. The old Reverend missing his son, but no one sends letter from Johannesburg. Finally, one day such letter comes, but it is not from son or sister, it is from another Reverend who says that his sister Gertrude is very ill and that he has to come immediately. Stephen Kumalo decides to go not only for sister but also he hopes to find his son Absalom. The Revered has to take all his money that he has been saving over the years and his wife has to forget about promised oven. It is very hard road ahead and it is very big and unfriendly city where danger can wait behind every corner.

Bibliography: p. 417-435

This standard work gives a history of each cult and sets out its doctrines, following the customary divisions of theology. The major teachings peculiar to each cult are examined in five appendices.

### Product Description Artists like Botticelli, Holbein, Leonardo, Durer, and Michelangelo and works such as the Last Supper fresco and the monumental marble statue of David, are familiar symbols of the Renaissance. But who were these artists, why did they produce such memorable images, and how would their original beholders have viewed these objects? Was the Renaissance only about great masters and masterpieces, or were women artists and patrons also involved? And what about the "minor" pieces that Renaissance men and women would have encountered in homes, churches and civic spaces? This Very Short Introduction answers such questions by considering both famous and lesser-known artists, patrons, and works of art within the cultural and historical context of Renaissance Europe. The volume provides a broad cultural and historical context for some of the Renaissance's most famous artists and works of art. It also explores forgotten aspects of Renaissance art, such as objects made for the home and women as artists and patrons. Considering Renaissance art produced in both Northern and Southern Europe, rather than focusing on just one region, the book introduces readers to a variety of approaches to the study of Renaissance art, from social history to formal analysis. ### About the Author **Geraldine A. Johnson** is Lecturer in the Department of the History of Art at Oxford University. She is the co-editor of _Picturing Women in Renaissance and Baroque Italy_ and the editor of _Sculpture and Photography: Envisioning the Third Dimension_. #genre

Botticelli, Holbein, Leonardo, Dürer, Michelangelo: the names are familiar, as are the works, such as the Last Supper fresco, or the monumental marble statue of David. But who were these artists, why did they produce such memorable images, and how would their original beholders have viewed these objects? Was the Renaissance only about great masters and masterpieces, or were'mistresses'also involved, such as women artists and patrons? And what about the'minor'-pieces that Renaissance men and women would have encountered in homes, churches and civic spaces? This exciting and stimulating volume will answer such questions by considering both famous and lesser-known artists, patrons and works of art within the cultural and historical context of Renaissance Europe. ABOUT THE SERIES: The Very Short Introductions series from Oxford University Press contains hundreds of titles in almost every subject area. These pocket-sized books are the perfect way to get ahead in a new subject quickly. Our expert authors combine facts, analysis, perspective, new ideas, and enthusiasm to make interesting and challenging topics highly readable.

Botticelli, Holbein, Leonardo, Dürer, Michelangelo: the names are familiar, as are the works, such as the Last Supper fresco, or the monumental marble statue of David. But who were these artists, why did they produce such memorable images, and how would their original beholders have viewed these objects? Was the Renaissance only about great masters and masterpieces, or were'mistresses'also involved, such as women artists and patrons? And what about the'minor'-pieces that Renaissance men and women would have encountered in homes, churches and civic spaces? This exciting and stimulating volume will answer such questions by considering both famous and lesser-known artists, patrons and works of art within the cultural and historical context of Renaissance Europe. ABOUT THE SERIES: The Very Short Introductions series from Oxford University Press contains hundreds of titles in almost every subject area. These pocket-sized books are the perfect way to get ahead in a new subject quickly. Our expert authors combine facts, analysis, perspective, new ideas, and enthusiasm to make interesting and challenging topics highly readable.

... onset depression (PO-MDD) is a common cause of distress and functional impairment, though efforts...

6. Spectral Crows in Hawai’i: Conservation and the Work of Inheritance was published in Extinction Studies on page 187.

### Product DescriptionArtists like Botticelli, Holbein, Leonardo, Durer, and Michelangelo and works such as the Last Supper fresco and the monumental marble statue of David, are familiar symbols of the Renaissance. But who were these artists, why did they produce such memorable images, and how would their original beholders have viewed these objects? Was the Renaissance only about great masters and masterpieces, or were women artists and patrons also involved? And what about the "minor" pieces that Renaissance men and women would have encountered in homes, churches and civic spaces? This Very Short Introduction answers such questions by considering both famous and lesser-known artists, patrons, and works of art within the cultural and historical context of Renaissance Europe. The volume provides a broad cultural and historical context for some of the Renaissance's most famous artists and works of art. It also explores forgotten aspects of Renaissance art, such as objects made for the home and women as artists and patrons. Considering Renaissance art produced in both Northern and Southern Europe, rather than focusing on just one region, the book introduces readers to a variety of approaches to the study of Renaissance art, from social history to formal analysis. ### About the Author

Botticelli, Holbein, Leonardo, Dürer, Michelangelo: the names are familiar, as are the works, such as the Last Supper fresco, or the monumental marble statue of David. But who were these artists, why did they produce such memorable images, and how would their original beholders have viewed these objects? Was the Renaissance only about great masters and masterpieces, or were'mistresses'also involved, such as women artists and patrons? And what about the'minor'-pieces that Renaissance men and women would have encountered in homes, churches and civic spaces? This exciting and stimulating volume will answer such questions by considering both famous and lesser-known artists, patrons and works of art within the cultural and historical context of Renaissance Europe. ABOUT THE SERIES: The Very Short Introductions series from Oxford University Press contains hundreds of titles in almost every subject area. These pocket-sized books are the perfect way to get ahead in a new subject quickly. Our expert authors combine facts, analysis, perspective, new ideas, and enthusiasm to make interesting and challenging topics highly readable.

The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material.

One of the most profound thinkers of modern history, Jean-Jacques Rousseau (1712-78) was a central figure of the European Enlightenment. He was also its most formidable critic, condemning the political, economic, theological, and sexual trappings of civilization along lines that would excite the enthusiasm of romantic individualists and radical revolutionaries alike. In this study of Rousseau's life and works Robert Wokler shows how his philosophy of history, his theories of music and politics, his fiction, educational and religious writings, and even his botany, were all inspired by visionary ideals of mankind's self-realization in a condition of unfettered freedom. He explains how, in regressing to classical republicanism, ancient mythology, direct communion with God, and solitude, Rousseau anticipated some post-modernist rejections of the Enlightenment as well. ABOUT THE SERIES: The Very Short Introductions series from Oxford University Press contains hundreds of titles in almost every subject area. These pocket-sized books are the perfect way to get ahead in a new subject quickly. Our expert authors combine facts, analysis, perspective, new ideas, and enthusiasm to make interesting and challenging topics highly readable.

One of the most profound thinkers of modern history, Jean-Jacques Rousseau (1712-78) was a central figure of the European Enlightenment. He was also its most formidable critic, condemning the political, economic, theological, and sexual trappings of civilization along lines that would excite the enthusiasm of romantic individualists and radical revolutionaries alike. In this study of Rousseau's life and works Robert Wokler shows how his philosophy of history, his theories of music and politics, his fiction, educational and religious writings, and even his botany, were all inspired by visionary ideals of mankind's self-realization in a condition of unfettered freedom. He explains how, in regressing to classical republicanism, ancient mythology, direct communion with God, and solitude, Rousseau anticipated some post-modernist rejections of the Enlightenment as well. ABOUT THE SERIES: The Very Short Introductions series from Oxford University Press contains hundreds of titles in almost every subject area. These pocket-sized books are the perfect way to get ahead in a new subject quickly. Our expert authors combine facts, analysis, perspective, new ideas, and enthusiasm to make interesting and challenging topics highly readable.

One of the most profound thinkers of modern history, Jean-Jacques Rousseau (1712-78) was a central figure of the European Enlightenment. He was also its most formidable critic, condemning the political, economic, theological, and sexual trappings of civilization along lines that would excite the enthusiasm of romantic individualists and radical revolutionaries alike. In this study of Rousseau's life and works Robert Wokler shows how his philosophy of history, his theories of music and politics, his fiction, educational and religious writings, and even his botany, were all inspired by visionary ideals of mankind's self-realization in a condition of unfettered freedom. He explains how, in regressing to classical republicanism, ancient mythology, direct communion with God, and solitude, Rousseau anticipated some post-modernist rejections of the Enlightenment as well. ABOUT THE SERIES: The Very Short Introductions series from Oxford University Press contains hundreds of titles in almost every subject area. These pocket-sized books are the perfect way to get ahead in a new subject quickly. Our expert authors combine facts, analysis, perspective, new ideas, and enthusiasm to make interesting and challenging topics highly readable.

The heritage of literature in the French language is rich varied, and extensive in time and space. This introduction presents this lively literary world by focusing on texts (epics novels, plays, poems, screenplays) that concern protagonists whose adventures and conflicts reveal shifts in literary and social practices.;1. Saints, werewolves, knights, and a pote maudit: allegiance and character in the Middle Ages -- 2. The last Roman, 'cannibals', giants, and heroines of modern life: antiquity and renewal -- 3. Society and its demands -- 4. Nature and its possibilities -- 5. Around the Revolution -- 6. The hunchback, the housewife, and the flneur -- 7. From Marcel to Rrose Selavy -- 8. The self-centred consciousness -- 9. French-speaking heroes without borders?

FIVE STARS from Doody's Star RatingsTMA step-by-step manual on the use of reconstructive surgery flaps – from planning to executionWritten by pioneering, world renowned flap surgeons, this is the quintessential manual on the use of reconstructive flaps - with detailed, easy-to-follow instructions. Overview chapters on each major anatomical area provide a general approach to reconstruction, with detailed tutorials on workhorse flaps in the A to Z section. The didactic text is enhanced with high quality operative photographs, illustrations, and videos, resulting in a resource that enables integration of these techniques into surgical practice.Key HighlightsProgressive intraoperative photos and superb illustrations guide the reader through safe and efficacious flap approachesPlanning and decision-making chapters cover basic principles, microsurgery, imaging, and an overview of current optionsFlaps section details the multivariate usages of microsurgical flaps, pedicled flaps, perforator flaps, and moreVideos focus on the anatomy and basic principles of technique for a range of common flaps further delineating and simplifying flap surgery for the practitionerThe Masterclasses section is packed with state of the art innovations, personal experience, and insights on managing challenging reconstructionsThis book is a stellar, step-by-step guide on the reconstruction of most anatomical defects using clinically proven flaps. It is an essential reference for practicing and trainee surgeons in general and specialized surgical disciplines. Plastic and reconstructive, trauma/burn, orthopaedic, otolaryngology-head and neck, and maxillofacial surgeons will greatly benefit from this comprehensive resource.

Discussing the 'real' Marquis de Sade from his mythical and demonic reputation, John Phillips examines Sade's life and work his libertine novels, his championing of atheism, and his uniqueness in bringing the body and sex back into philosophy.

A Very Short Introduction Preface 15 Acknowledgements 17 List of illustrations 19 1 Beyond the myth: the real Marquis de Sade 23 2 Man of letters 35 3 Martyr of atheism 58 4 Sade and the French Revolution 71 5 Theatres of the body 89 6 Representations of the feminine 114 7 Apostle of freedom 144 Further reading 157 References 164 Index 168

Discussing the 'real' Marquis de Sade from his mythical and demonic reputation, John Phillips examines Sade's life and work his libertine novels, his championing of atheism, and his uniqueness in bringing the body and sex back into philosophy.

Discussing the 'real' Marquis de Sade from his mythical and demonic reputation, John Phillips examines Sade's life and work his libertine novels, his championing of atheism, and his uniqueness in bringing the body and sex back into philosophy.

A Very Short Introduction

"John E. Woods is revising our impression of Thomas Mann, masterpiece by masterpiece."  --The New Yorker "Doctor Faustus is Mann's deepest artistic gesture. . . . Finely translated by John E. Woods." --The New Republic Thomas Mann's last great novel, first published in 1947 and now newly rendered into English by acclaimed translator John E. Woods, is a modern reworking of the Faust legend, in which Germany sells its soul to the Devil. Mann's protagonist, the composer Adrian Leverkühn, is the flower of German culture, a brilliant, isolated, overreaching figure, his radical new music a breakneck game played by art at the very edge of impossibility. In return for twenty-four years of unparalleled musical accomplishment, he bargains away his soul--and the ability to love his fellow man. Leverkühn's life story is a brilliant allegory of the rise of the Third Reich, of Germany's renunciation of its own humanity and its embrace of ambition and nihilism. It is also Mann's most profound meditation on the German genius--both national and individual--and the terrible responsibilities of the truly great artist. **

"John E. Woods is revising our impression of Thomas Mann, masterpiece by masterpiece."  --The New Yorker "Doctor Faustus is Mann's deepest artistic gesture. . . . Finely translated by John E. Woods." --The New Republic Thomas Mann's last great novel, first published in 1947 and now newly rendered into English by acclaimed translator John E. Woods, is a modern reworking of the Faust legend, in which Germany sells its soul to the Devil. Mann's protagonist, the composer Adrian Leverkühn, is the flower of German culture, a brilliant, isolated, overreaching figure, his radical new music a breakneck game played by art at the very edge of impossibility. In return for twenty-four years of unparalleled musical accomplishment, he bargains away his soul--and the ability to love his fellow man. Leverkühn's life story is a brilliant allegory of the rise of the Third Reich, of Germany's renunciation of its own humanity and its embrace of ambition and nihilism. It is also Mann's most profound meditation on the German genius--both national and individual--and the terrible responsibilities of the truly great artist. **

"John E. Woods is revising our impression of Thomas Mann, masterpiece by masterpiece." --The New Yorker"Doctor Faustus is Mann's deepest artistic gesture. . . . Finely translated by John E. Woods." --The New RepublicThomas Mann's last great novel, first published in 1947 and now newly rendered into English by acclaimed translator John E. Woods, is a modern reworking of the Faust legend, in which Germany sells its soul to the Devil. Mann's protagonist, the composer Adrian Leverkühn, is the flower of German culture, a brilliant, isolated, overreaching figure, his radical new music a breakneck game played by art at the very edge of impossibility. In return for twenty-four years of unparalleled musical accomplishment, he bargains away his soul--and the ability to love his fellow man. Leverkühn's life story is a brilliant allegory of the rise of the Third Reich, of Germany's renunciation of its own humanity and its embrace of ambition and nihilism. It is also Mann's most profound meditation on the German genius--both national and individual--and the terrible responsibilities of the truly great artist