From Clinical Pharmacology to Pharmaceutical Medicine

1. From Clinical Pharmacology to Pharmaceutical Medicine Prof. Milica Prostran, MD PhD

2. "Once upon a time there was a tribe called "Pharmacologists". They dwelled in a place called Academe and busied away in laboratories, carryng out complicated investigations to discover how medicines made people better and looking for newer and better medicines. To do this was very difficult so they studied all the old writings for clues.... In this way, 30-40 new medicines became available each year... Many thought that the progress was slow, as well as expensive, and still there were many pressing needs for which little treatment was available each year. A magic formula was needed...“ R & D

3. Drug discovery and development: The clinical pharmacologist’s view The toxicologist’s view The regulator’s view R & D

4. "Drug discovery and development is one of the most complex processes undertaken by man. It involves close teamwork by scientists from many different disciplines and, despite their best efforts, the majority of projects fail to achive their goal of creating a new therapeutic agent." R & D

5. Drug discovery and development - some facts: Only 1-2% of early exploratory studies at the bench ever make it to a marketed product Even when a compound progresses to the point of 1st administration to man between 70% and 95% fail depending upon the degree of novelty of the project: Pioneer or unprecented projects: There is no existing marketed agent Fast followers or precedented projects: There is existing marketed agent R & D

6. Drug discovery and development - some facts: The time period from the inception of a new idea to marketing a product derived from it is very long, a minimum of 10 years, and often considerably longer Enormous and increasing costs, up to $900 million Only 3 of 10 marketed drugs return their R & D investments, thus providing considerable motivation to develop "blockbusters": The global market for pharmaceuticals in 2006 was estimated at about $640 billion The 2004 sales of the top-selling drug worldwide (atorvastatin-Lipitor®) exceeded $10 billion R & D

7. Drug discovery and development - some facts: One of the most important ways of deciding whether or not a compound should progress lies in whether it has achieved minimum requirements set out in the target product profile (TPP) R & D

8. Drug discovery and development - some facts: TPP is a list of requirements: Scientific Medical Commercial R & D

9. Drug discovery and development - some facts: "Lead" is a molecule that is drug-like Lead optimization is one of the most crucial steps in drug development R & D

10. Drug discovery and development - some facts: The medicinal chemist will seek to do four things: Improve the activity against the primary target Minimize activity against closely related targets: The aim is usually a minimum of 100-fold selectivity 1000-fold selectivity is better as, for poorly understood reasons, in vivo selectivity is often less than that in vitro Optimize the pharmacokinetic properties Avoidance of toxicity R & D

11. Drug discovery and development - some facts: Preclinical studies: Pharmacokinetic studies Pharmacodynamic studies: In vitro In vivo Toxicology Clinical studies (I-IV) R & D

12. Drug discovery and development - some facts: Pharmacodynamic studies: In vitro In vivo R & D

13. In vitro: Prostran M, Varagic VM. The effects of local anaesthetics on the isometric contraction of the isolated hemidiaphragm of the rat. Arch Int Pharmacodyn 1981; 250: 30-9. Prostran M, Varagic VM. The effect of forskolin on the isometric contraction of the isolated hemidiaphragm of the rat. Br J Pharmacol 1986; 88: 791-7. Prostran M, Varagic VM. Interactions of 5'-N-ethylcarboxamide adenosine (NECA), aminophylline and dipropyl-phenyl-xanthine (XAC) on the isolated guinea-pig atria. Arch Int Pharmacodyn Ther 1988; 294: 137-48. Vujnov S, Prostran M, Savic JD, Varagic VM, Lovric M. Beta-adrenergic receptors and catecholamines in the rat heart during tourniquet trauma. Circ Shock 1992; 36: 38-44. Prostran M, Todorovic Z, Varagic VM. Some new evidence on antifatigue action of aminophylline on the isolated hemidiaphragm of the rat. Gen Pharmacol 1993; 24: 225-32. R & D

15. In vivo: Varagic VM, Prostran MS. Modulating effect of adenosine on the hypertensive response to physostigmine. Arch Int Pharmacodyn Ther 1991; 311: 144-54. Vuckovic SM, Tomic MA, Stepanovic-Petrovic RM, Ugresic N, Prostran MS, Boskovic B. The effects of alpha2-adrenoceptor agents on anti-hyperalgesic effects of carbamazepine and oxcarbazepine in a rat model of inflammatory pain. Pain 2006;125(1-2):10-9. Todorovic Z, Nesic Z, Stojanovic R, Basta-Jovanovic G, Radojevic-Skodric S, Velickovic R, Chatterjee PK, Thiemermann C, Prostran M. Acute protective effects of simvastatin in the rat model of renal ischemia-reperfusion injury: it is never too late for the pretreatment. J Pharmacol Sci 2008; 107(4): 465-70. R & D

16. Clinical studies: Kovacevic I, Pokrajac M, Miljkovic B, Jovanovic D, Prostran M. Comparison of liquid chromatography with fluorescence detection to liquid chromatography-mass spectrometry for the determination of fluoxetine and norfluoxetine in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2006;830(2):372-6. Divac N, Jasovic-Gasic M, Samardzic R, Lackovic M, Prostran M. Antipsychotic polypharmacy at the University Psychiatric Hospital in Serbia. Pharmacoepidemiol Drug Saf 2007;16(11):1250-1. Vezmar S, Miljkovic B, Vucicevic K, Timotijevic I, Prostran M, Todorovic Z, Pokrajac M. Pharmacokinetics and efficacy of fluvoxamine and amitriptyline in depression. J Pharmacol Sci 2009; 110(1): 98-104. Vucicevic K, Miljkovic B, Pokrajac M, Prostran M, Martinovic Z, Grabnar I. The influence of drug-drug interaction and patients' characteristics on valproic acid's clearance in adults with epilepsy using nonlinear mixed effects modeling. Eur J Pharm Sci 2009; 38(5): 512-8. R & D

17. What does the future bring? From Clinical Pharmacology to Pharmaceutical Medicine

18. Pharmaceutical Medicine: ECPM, University of Basel, CH-4066 Basel From Clinical Pharmacology to Pharmaceutical Medicine

19. www.pharmatrain.eu From Clinical Pharmacology to Pharmaceutical Medicine

20. Some facts on this project: School of Medicine, University of Belgrade, Serbia is a member of this EC project: Participant Number 16 15 Short name UBG The project started at the beginning of 2009 Prof. Milica Prostran is a member of the steering committee as well as of the following WPs: WP-3: Harmonisation of Syllabus and Training Principles WP-5: Geographical Extension of Training Sites and Network From Clinical Pharmacology to Pharmaceutical Medicine

21. "The European Commission stated in its overall evaluation that especially important points are: Creating an inclusive environment open at all times to integrating existing or evolving educational programs in Europe Developing a plan to meet the needs of all 27 Member States, including student recruitment and facilitation Adopting an e-learning platform conform to program needs." From Clinical Pharmacology to Pharmaceutical Medicine

22. "The European Commission is convinced that the PharmaTrain will contribute significantly to the advancement of pharmaceutical medicine education in Europe: The main objective of PharmaTrain is to create a new multimodular Diploma/Master Level Program for advanced studies in Pharmaceutical Medicine/Drug Development Sciences based on an updated Syllabus of Pharmaceutical Medicine." From Clinical Pharmacology to Pharmaceutical Medicine