Drugs Looking for Diseases: Innovative Drug Research and the Development of the Beta Blockers and the Calcium Antagonists (Developments in Cardiovascular Medicine)

1. 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.- 2.5.2.1..The classification of drugs.- 2.5.2.2. Incursion of drug profiles into disease profiles.- 2.5.2.3. The nature of drug characteristics.- 2.5.3. The concept of disease profile.- 2.5.3.1. Disease profiles as pigeon holes of medical knowledge.- 2.5.3.2. The fundamental basis of taxonomy in medicine.- 2.5.3.3. Convergent and divergent forces in clinical taxonomy.- 2.5.3.4. 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.- 4.2.4.1. A "clean" drug.- 4.2.4.2. The rapid expansion of a successful drug.- 4.2.4.3. Endangered drug.- 4.2.5. The development of practolol.- 4.2.5.1. Practolol: a tool in industrial research.- 4.2.5.2. Selectivity in industrial and academic research.- 4.2.5.3. 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