Future Directions

It has been argued8 that general anesthesia cannot be adequately explained until there is a clearer understanding of the phenomenon of consciousness and the associated states of awareness and sleep. Examination of individual components of anesthesia, immobility, antinociception, and amnesia underlines the need for an integrated approach to such understanding since, for instance, pain can lead to increased awareness. The search for discrete mechanisms for anesthetics of all three classes - inhalation, parenteral and local - is gradually advancing but has yet to be used for the de novo discovery of new anesthetic agents. The ability to reconcile the unitary hypothesis of anesthesia with multiple molecular targets will be an interesting research challenge and will require that the sophisticated molecular modeling of anesthetic interactions with membranes extends beyond artificial, reductionistic constructs,3,10,16,17,25,26 that, although eminently interesting, add little to advancing research in the area without a consideration of the effects of anesthetics in more complex native membrane systems.


1. Evers, A. S.; Crowder, M.; Balser, J. R. General Anesthetics. In Goodman and Gilman's The Pharmacological Basis of Therapeutics, 11th ed.; Brunton, L. L., Lazo, J. S., Parker, K. L., Eds.; McGraw Hill: New York, 2006, pp 341-368.

3. Forman, S. A.; Raines, D. E.; Miller, K. W The Interactions of General Anesthetics with Membranes. In Anesthesia: Biologic Foundations; Yaksh, T L., Maze, M., Lynch, C., Biebuyck, J. F, Zapol, W M., Saidman, L. J., Eds.; Lippincott-Raven: Philadelphia, PA, 1997, pp 5-18.

4. Lydic, R.; Baghdoyan, H. Cholinergic Contributions to the Control of Consciousness. In Anesthesia: Biologic Foundations; Yaksh, T. L., Maze, M., Lynch, C., Biebuyck, J. F., Zapol, W. M., Saidman, L. J., Eds.; Lippincott-Raven: Philadelphia, PA, 1997, pp 433-450.

5. Nelson, L. E.; Guo, T. Z.; Lu, J.; Saper, C. B.; Franks, N. P; Maze, M. Nat. Neurosci. 2002, 5, 979-984.

6. Arhem, P.; Klement, G; Nilsson, J. Neuropsychopharmacology 2003, 28, S40-S47.

9. Hemmings, H. C., Jr.; Akabas, M. H.; Goldstein, P. A.; Trudell, J. R.; Orser, B. A.; Harrison, N. L. Trends Pharmacol. Sci. 2005, 26, 503-510.

10. Yamakura, T; Bertaccini, E.; Trudell, J. R.; Harris, R. A. Annu. Rev. Pharmacol. Toxicol. 2001, 41, 23-51.

11. Tomlin, S. I.; Jenkins, A.; Lieb, Wi R.; Franks, N. P. Anesthesiology 1998, 88, 708-717.

13. Catterall, W A.; Goldin, A. L.; Waxman, S. G. Pharmacol. Rev. 2005, 57, 397-409.

14. Catterall, W A.; Mackie, K. Local Anesthetics. In Goodman and Gilman's The Pharmacological Basis of Therapeutics, 11th ed.; Brunton, L. L., Lazo, J. S., Parker, K. L., Eds.; McGraw Hill: New York, 2006, pp 369-386.

15. Yaksh, T L.; Rudy, T A. Science 1976, 192, 1357-1358.

16. Eckenhoff, R. G.; Johnasson, J. S. Inhalation Anesthetic Interactions with Proteins. In Anesthesia: Biologic Foundations; Yaksh, T. L., Maze, M., Lynch, C., Biebuyck, J. F, Zapol, W M., Saidman, L. J., Eds.; Lippincott-Raven: Philadelphia, PA, 1997, pp 19-32.

17. Liu, R.; Loll, P. J. Eckenhoff, R. G. FASEB J. 2005, 19, 567-576.

18. Peet, M. Prostaglandin, Leukotrienes, Essential Fatty Acids 2004, 70, 417-422.

19. Kemperman, R. F J.; Veurink, M.; van der Wal, T; Knegtering, H.; Bruggeman, R.; Fokkema, M. R.; Kema, I. P; Korf, J.; Muskiet, F A. J. Prostaglandin, Leukotrienes, Essential Fatty Acids 2006, 74, 75-85.

20. Firestone, L. L.; Alifimoff, J. K.; Miller, K. W Mol. Pharmacol. 1994, 46, 508-515.

21. Leal, S. M.; Evers, A. S. Anesthesiology 1994, 81, A897.

22. Taylor, J. M.; Jacob-Mosier, G. G.; Lawton, R. G.; VanDort, M.; Neubig, R. R. J. Biol. Chem. 1996, 271, 3336-3339.

23. Leite, J. F; Blanton, M. P.; Shahgholi, M.; Dougherty, D. A.; Lester, H. A. Proc. Natl Acad. Sci. USA 2003, 100, 13054-13059.

24. Forman, S. A.; Miller, K. Wi; Yellen, G. Mol. Pharmacol. 1995, 48, 574-581.

25. Tang, P.; Xu, Y Proc. Natl Acad. Sci. USA 2002, 99, 16035-16040.

26. Liu, Z.; Xu, Y; Tang, P Biophys. J. 2005, 88, 3784-3791.

27. Franks, N. P; Lieb, W R. Nature 1994, 367, 607-614.

28. Rudolph, U.; Antkowiak, B. Nat. Rev. Neurosci. 2004, 5, 709-720.

29. Mihic, S. J.; Ye, Q.; Wick, M. J.; Koltchine, V V.; Krasowski, M. D.; Finn, S. E.; Mascia, M. P.; Valenzuala, C. F; Hanson, K. K.; Greenblatt, E. P et al. Nature 1997, 389, 385-389.

30. Franks, N. P Br. J. Pharmacol. 2006, 141, S72-S81.

31. Wakamori, M.; Ikemoto, Y; Akaike, N. J. Neurophysiol. 1991, 66, 2014-2021.

32. Jones, M. V; Harrison, N. L. J. Neurophysiol. 1993, 10, 1339-1349.

33. Cottrell, G. A.; Lambert, J. J.; Peters, J. A. J. Neurosci. 1987, 90, 491-500.

34. Krasowski, M. D.; Jenkins, A.; Flood, P; Kung, A. Y; Hopfinger, A. J.; Harrison, N. L. J. Pharmacol. Exp. Ther. 2001, 291, 338-351.

35. Gutman, G. A.; Chandy, K. G.; Grissmer, S.; Lazdunski, M.; McKinnon, D.; Pardo, L. A.; Robertson, G. A.; Rudy, B.; Sanguinetti, M. C.; Stühmer, W et al. Pharmacol. Rev. 2005, 51, 473-508.

36. Harris, T.; Graber, A. R.; Covarrubias, M. Am. J. Physiol. Cell Physiol. 2003, 285, C788-C796.

37. Patel, A. J.; Honore, E. Anesthesiology 2001, 95, 1013-1021.

38. Catterall, W A.; Perez-Reyes, E.; Snutch, T P.; Striessnig, J. Pharmacol Rev. 2005, 51, 411-425.

39. Rehberg, B.; Xiao, Y-H.; Duch, D. S. Anesthesiology 1996, 84, 1223-1233.

40. Franks, N. P; Lieb, W R. Science 1991, 254, 427-430.

41. Zhang, L.; Oz, M.; Stewart, R. R.; Peoples, R. W; Weight, F F Br. J. Pharmacol. 1997, 120, 574-581.

42. Strois, J. E.; Lynch, C., III; Bayliss, D. A. J. Physiol. 2002, 541, 717-729.

43. Wan, X.; Mathers, D. A.; Puil, E. Neuroscience 2005, 121, 947-958.

44. Cacheaux, L. P; Topf, N.; Tibbs, G. R.; Schaefer, U. R.; Levi, R.; Harrison, N. L.; Abbott, G. W; Goldstein, PA. J. Pharmacol Exp. Ther. 2005, 315, 517-525.

45. Dickenson, R.; White, I.; Lieb, W R.; Franks, N. P Anesthesiology 2000, 93, 837-843.

46. Gustafsson, L. L.; Ebling, W F; Osaki, E.; Stanski, D. R. Anesthesiology 1996, 84, 415-442.

47. Gottschalk, A.; Smith, D. S. Am. Fam. Phys. 2001, 63, 1979-1986.

48. Goto, T; Nakata, Y; Morita, S. Anesthesiology 2003, 98, 1-2.

49. Bhana, N.; Goa, K. L.; McClellan, H. J. Drugs 2000, 59, 263-268.

50. Jalonen, J.; Hynynen, M.; Kuitunen, A.; Heikkila, H.; Perttila, J.; Salmenpera, M.; Valtonen, M.; Aantaa, R.; Kallio, A. Anesthesiology 1997, 86, 331-345.

51. Flood, P Curr. Opin. Pharmacol. 2005, 5, 322-327.

52. Shephard, D. A. E. Can. J. Anesth. 2005, 52, 238-248.

53. Nadeson, R.; Goodchild, C. S. Br. J. Anaesth. 2001, 86, 704-708.

54. Naguib, M.; Baker, M. T.; Spadoni, G.; Grgegerson, M. Anesth. Analg. 2003, 91, 763-768.


T A Bowdle, MD, PhD, obtained his undergraduate education at University of California at Davis and BS degree in 1974. He obtained his graduate education at University of Washington; Medical Scientist Training Program, MD, and PhD (Pharmacology) degrees in 1980; his internship at Virginia Mason Medical Center, 1980-81 and Anesthesiology residency at University of Washington, 1980-83. He is currently a professor of anesthesiology and pharmaceutics (adjunct), Chief of the Division of Cardiothoracic Anesthesiology at University of Washington. Major interests are local anesthetic and opioid pharmacology; pharmacokinetics; clinical outcomes (drug administration errors, complications of central venous catheter placement); depth of anesthesia monitoring.

L J S Knutsen began his research career at Glaxo in Ware, Herts, UK having completed an MA in chemistry at Christ Church, Oxford, in 1978. While at Glaxo, he completed a PhD in nucleoside chemistry joining Novo Nordisk in Denmark in 1986. There he led the project that identified tiagabine, a marketed anticonvulsant acting by blocking GABA uptake. In 1997, he joined Vernalis (Cerebrus) in the UK, initiating the adenosine A2A antagonist project that led to V2006, currently in clinical trials with Biogen-IDEC for Parkinson's disease. He joined Ionix Pharmaceuticals Ltd., in Cambridge, UK in 2002 as Director of Chemistry. Dr Knutsen joined the CNS Medicinal Chemistry group at Cephalon Inc., in 2006. He has over 35 peer-reviewed publications and 18 issued US patents.

Michael Williams, PhD, DSc, received his PhD (1974) from the Institute of Psychiatry and his DSc degree in pharmacology (1987) both from the University of London. Dr Williams has worked in the US-based pharmaceutical industry for 30 years at Merck, Sharp and Dohme Research Laboratories, Nova Pharmaceutical, CIBA-Geigy and Abbott Laboratories. He retired from the latter in 2000 and after serving as a consultant with various biotechnology/ pharmaceutical/venture capital companies in the US and Europe, joined Cephalon, Inc. in West Chester, in 2003 where he is vice president of Worldwide Discovery Research. He has published some 300 articles, book chapters, and reviews, and is an adjunct professor in the Department of Molecular Pharmacology and Biological Chemistry at the Feinberg School of Medicine, Northwestern University, Chicago, IL.

© 2007 Elsevier Ltd. All Rights Reserved Comprehensive Medicinal Chemistry II

No part of this publication may be reproduced, stored in any retrieval system or transmitted ISBN (set): 0-08-044513-6 in any form by any means electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers ISBN (Volume 6) 0-08-044519-5; pp. 351-367

Diabetes Sustenance

Diabetes Sustenance

Get All The Support And Guidance You Need To Be A Success At Dealing With Diabetes The Healthy Way. This Book Is One Of The Most Valuable Resources In The World When It Comes To Learning How Nutritional Supplements Can Control Sugar Levels.

Get My Free Ebook

Post a comment