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We all know how much time, effort and money it takes to develop a new drug. Hundreds of chemical compounds have to be synthesized and thousands of different activities in biology, physiology, pharmacology, clinical investigation, management and marketing have to be initiated and coordinated. Each new drug starts a voyage of discovery through an unmapped terrain which is shrouded in mist and beset by pitfalls, as Dr. Rein Vos puts it in his absorbing inside story of the development of the beta-adrenoceptor blocking agents and the calcium antagonists. Indeed we know, for example, how long it took before the theory of Ahlquist of the alpha and beta adrenergic receptors was widely accepted. Similarly, it suffices to memorize shortly the difficulty of expanding the new concept of calcium antagonism through the national German boundaries into the world. This shows how laborious and complex pharmaceutical progress is, and we all will benefit from a deeper understanding of the process of innovative drug research.
Table of Contents1. The controlled clinical trial a model for the intricate relationships between clinical medicine and drug research.- 1.1. Introduction.- 1.2. The evolution of the controlled clinical trial (CCT).- 1.3 The implementation of the controlled clinical trial in drug research.- 1.4. Criticism of the classical view of the controlled clinical trial.- 1.5. Conclusions.- 2. The architecture of drug discovery.- 2.1. Introduction.- 1. The discovery process.- 2.2. Current views of drug discovery.- 2.2.1. Basic concepts in drug discovery.- 2.2.2. Basic epistemologies in drug discovery.- 2.3. Scientific discovery from the viewpoint of cognitive science.- 2.4. The drug discovery process revisited.- 2. The representation of knowledge about drugs and diseases.- 2.5. An epistemological analysis of the concept of drug and disease profiles.- 2.5.1. Introduction.- 2.5.2. The concept of drug profile.- 22.214.171.124..The classification of drugs.- 126.96.36.199. Incursion of drug profiles into disease profiles.- 188.8.131.52. The nature of drug characteristics.- 2.5.3. The concept of disease profile.- 184.108.40.206. Disease profiles as pigeon holes of medical knowledge.- 220.127.116.11. The fundamental basis of taxonomy in medicine.- 18.104.22.168. Convergent and divergent forces in clinical taxonomy.- 22.214.171.124. The translation of everyday medical language into the structure of profiles.- 2.5.4. Conclusions.- 3. A set-theoretical model of drug discovery.- 2.6. A definition of the concept of profile in terms of set theory.- 2.6.1. Introduction.- 2.6.2. The first aspect of a profile: membership.- 2.6.3. The second aspect of the concept of profile: values of the disease characteristics.- 2.6.4. The third aspect of the concept of profile: ranking order of characteristics.- 2.6.5. Conclusions.- 2.7. The drug discovery process a set-theoretical model.- 2.7.1. Introduction.- 2.7.2. A naive definition.- 2.7.3. First adjustment of the naive defenition: structural and functional characteristics of drugs.- 2.7.4. Second adjustment of the naive defenition: disease characteristics.- 2.7.5. The improvement of toxic effects of drugs: positive and negative aspects and their judgment.- 2.7.6. Conclusions.- 3.Experimental and therapeutic profiling in drug innovation: the early history of the beta blockers.- 3.1. Introduction.- 3.2. Historical overview of the development of the beta blockers.- 3.3. From Dale to Ahlquist: a new methodology in pharmacology.- 3.4. Change in the concepts of agonist and antagonist.- 3.5. Experimental and therapeutic profiling in drug innovation.- 3.5.1. Cardiac arrhythmias.- 3.5.2. Angina pectoris.- 3.6. Conclusions.- 4. Industrial research and beta blockade.- 4.1. Introduction.- 4.2. Beta blocker research at Imperial Chemical Industries (ICI).- 4.2.1. The early phase.- 4.2.2. The birth of pronethalol.- 4.2.3. The demise of pronethalol.- 4.2.4. The development of propranolol.- 126.96.36.199. A “clean” drug.- 188.8.131.52. The rapid expansion of a successful drug.- 184.108.40.206. Endangered drug.- 4.2.5. The development of practolol.- 220.127.116.11. Practolol: a tool in industrial research.- 18.104.22.168. Selectivity in industrial and academic research.- 22.214.171.124. The therapeutic interest.- 4.3. The beta blocker project of Eli Lilly & Co..- 4.4. The beta blocker project of Mead Johnson.- 4.5. The beta blocker project of AB Hässle.- 4.5.1. The early phase.- 4.5.2. Intrinsic sympathomimetic activity of alprenolol.- 4.5.3. The profiling of alprenolol.- 4.5.4. Selective beta blockade.- 4.6. The beta blocker project at CIBA.- 4.7. Conclusions.- 5. Verapamil: dying drug or sleeping beauty?.- 5.1 Introduction.- 5.2 The early history of verapamil.- 5.3 Verapamil: a coronary vasodilator?.- 5.4 Verapamil: a beta blocker?.- 5.5. Verapamil: a calcium antagonist! The elucidation of verapamil’s mechanism of action by Fleckenstein.- 5.6. Citation analysis of the concept of calcium antagonism elaborated by Fleckenstein.- 5.7. The application of the theory of drug and disease profiles.- 5.7.1. Changing views on the basic action of verapamil.- 5.7.2. The cardio-depressive effects of verapamil..- 5.8. Conclusions.- 6. Metamorphosis of a disease Profiles of angina pectoris in Anglo-American medicine.- 6.1. Introduction.- 6.2. Anglo-American medical views of angina pectoris.- 6.3. Disease profiles of angina pectoris in Anglo-American medicine: cognitive dimensions..- 6.4. Disease profiles of angina pectoris in Anglo-American medicine: social dimensions.- 6.5. Anti-anginal drugs in the light of changing views of angina pectoris.- 6.6. Conclusions.- 7. Targeting in drug research and the medical scene The beta blocker project at Boehringer against the background of different views in German and Anglo-American medicine.- 7.1 Introduction.- 1. The medical scene different views in German and Anglo-American medicine.- 7.2.1 The coronary vasodilator concept.- 126.96.36.199. Introduction.- 188.8.131.52. The early history of the coronary vasodilator concept.- 184.108.40.206. The rise and decline of the coronary vasodilator concept in Anglo-American medicine.- 220.127.116.11. The coronary vasodilator concept - a firmly rooted principle in German medicine.- 18.104.22.168 Bibliometrical analysis.- 22.214.171.124 Conclusions.- 7.2.2. Medical views about heart failure.- 126.96.36.199. Introduction.- 188.8.131.52 Anglo-American medical views about congestive heart failure: Starling’s Law of the Heart..- 184.108.40.206. German medical views about heart failure: The master of the circulation?.- 220.127.116.11. Three clinical profiles of heart failure.- 18.104.22.168. Disease profiles of heart failure in Anglo-American and German medicine.- 22.214.171.124. Conclusions.- 7.2.3. Angina pectoris and coronary insufficiency in German medicine.- 126.96.36.199. Introduction.- 188.8.131.52. Coronary insufficiency.- 184.108.40.206. Organic and functional factors in German clinical taxonomy.- 2. The influence of medical perceptions on targeting in drug research.- 7.3. The beta blocker project at Boehringer Ingelheim.- 3. Application of the theory of drug and disease profile.- 7.4. Theoretical analysis of the Boehringer project against the background of medical views about angina pectoris and heart failure.- 7.5. Conclusions.- 8.Search processes, profiles and therapeutic practice in drug discovery.- 8.1. Introduction.- 8.2. The search process in drug discovery.- 8.3. Evaluation of the theory of drug discovery.- 8.3.1. Introduction.- 8.3.2. The epistemological status of the concept of profile.- 8.3.3. Is the discovery process explicable in terms of profiles and rules?.- 8.4. Practice - the contribution to drug discovery.- 8.4.1. Introduction.- 8.4.2. The conflict between controlled clinical trial and casual experience in therapeutics.- 220.127.116.11. Toulmin’s epistemological map of medicine.- 18.104.22.168. Application of Toulmin’s map on the conflict between controlled clinical trial and casual experience in medicine.- 22.214.171.124. Pragmatic attitude towards the controlled clinical trial.- 126.96.36.199. Dissection of the strong interpretation of the normative claim about the CCT.- 8.4.3. Therapeutic treatment based on the individual patient.- 8.4.4. Accumulated experience and therapeutic intervention.- 8.4.5. Further explication of practice as a source of new knowledge.- 8.5. Conclusions.- 9. The enigma of drug discovery.- Notes.- 1.- 2.- 3.- 4.- 5.- 6.- 7.- 8.- 9.- References.- Appendices.- Appendix I. The ranking order aspect of the concept of profile.- Appendix II. Bibliometrical analysis of the impact of Fleckenstein’s concept of calcium antagonism.- Appendix III. Bibliometrical analysis of Charlier’s “Antianginal Drugs”.- Name Index.