DOI QR코드

DOI QR Code

Investigation of the Pharmacological Mechanisms and the R&D of Medical Countermeasures Against Nerve Agent Poisoning

신경작용제 해독제의 약리기전 및 연구개발

  • Received : 2011.07.20
  • Accepted : 2011.09.16
  • Published : 2011.10.05

Abstract

Nerve agents are irreversible inhibitors of the cholinesterase enzyme. Exposure causes a progression of toxic signs, including hypersecretions, fasciculations, tremor, convulsions, respiratory distress, epileptiform seizures, brain injuries and death. A combined regimen of prophylaxis and therapy is the most effective medical countermeasure for dealing with the threat of nerve agent poisoning to military personnel. In this paper, the author investigated the updated technologies regarding various pre- and post-treatment drugs for nerve agents detoxification which are under development in several countries including Korea. Some characteristics of active ingredients in the formulations of drugs, their action mechanisms, and effectiveness were analyzed. Additionally, part of experimental data on the transdermal patch studied in ADD using beagle dogs was introduced.

Keywords

References

  1. McDonough, J. H., Jr., Shih, T.-M.,. "Pharmacological Modulation of Soman-Induced Seizures", Neurosci. Biobehav. Rev., Vol. 17, pp. 203-215, 1993. https://doi.org/10.1016/S0149-7634(05)80151-4
  2. Shih, T.-M., Koviak, T. A., Capricio, B. R., "Anti- Convulsants for Poisoning by the Organophosphorus Compound Soman : Pharmacological Mechanisms", Neurosci. Biobehav. Rev., Vol. 15, pp. 349-362, 1991. https://doi.org/10.1016/S0149-7634(05)80028-4
  3. Kim, Y.-B., Hur, G.-H., Shin, S., Sok, D.-E., Kang, J.-K., Lee Y.-S., "Organophosphate-Induced Brain Injuries : Delayed Apoptosis Mediated by Nitric Oxide", Environ. Toxicol. Pharmacol., Vol. 7, pp. 147-152, 1999. https://doi.org/10.1016/S1382-6689(99)00006-X
  4. McDonough, J. H., Jr., Jaax, N. K., Crowley, R. A., Mays, M. Z., Modrow, H. E., "Atropine and Diazepamtherapy Protects Against Soman-Induced Neural and Cardiac Pathology", Fund. Appl. Toxicol., Vol. 13, pp. 256-276, 1989. https://doi.org/10.1016/0272-0590(89)90262-5
  5. Tryphonas, L., Clement, J. G., "Histomorphogenesis of Soman-Induced Encephalocardiomyopathy in Sprague-Dawley Rats", Toxicol. Pathol., Vol. 23, pp. 393-409, 1995. https://doi.org/10.1177/019262339502300316
  6. Shih, T.-M., Duniho, S. M., McDonough, J. H., "Control of Nerve Agent-Induced Seizures is Critical for Neuroprotection and Survival", Toxicol. Appl. Pharmacol., Vol. 188, pp. 69-80, 2003. https://doi.org/10.1016/S0041-008X(03)00019-X
  7. Spradling, K. D., Dillman, J. F., "Toxicology of Chemical Warfare Nerve Agents", Advances in Molecular Toxicology, Vol. 5, pp. 111-144, 2011. https://doi.org/10.1016/B978-0-444-53864-2.00003-7
  8. Myhrer, T., "Prophylactic and Therapeutic Measures in Nerve Agent Poisoning", Handbook of Toxicology of Chemical Warfare Agents, pp. 965-975, 2009.
  9. Joosen, M. J. A., Schans, M. J., Helden, H. P. M., "Efficacy of Combined Atropine, Obidoxime and Diazepam Treatment", Chem. Bio. Int., Vol. 188 (Issue 1, No. 6), pp. 255-263, 2010. https://doi.org/10.1016/j.cbi.2010.06.010
  10. Vrdoljak, A. L., Calic, M., Radic, B., Berend, S., Jun, D., Kuca, K., Kovarik, Z., "Pretreatment with Pyridium Oximes Improves Antidotal Therapy Against Tabun Poisoning", Toxicol., Vol. 228, pp. 41-50, 2006. https://doi.org/10.1016/j.tox.2006.08.012
  11. Kadar, T., Shapira, S., Cohen, G., Sahar, R., Alkalay, D., Raveh, L., "Sarin-Induced Neurophathology in Rats", Human Exp. Toxicol., Vol. 14, pp. 252-259, 1995. https://doi.org/10.1177/096032719501400304
  12. Philippens, I. H. C. H. M., Melchers, B. P. C., DeGroot, D. M. G., Wolthuis, O. I., "Behavioral Performance, Brain Histology and EEG Sequela After Immediate Combined Atropine/Diazepam Treatment of Soman-Intoxicated Rats", Pharmacol. Biochem. Behav., Vol. 42, pp. 711-719, 1992. https://doi.org/10.1016/0091-3057(92)90019-C
  13. McDonough, J. H., Jr., Dochterman, L. W., Smith, C. D., Shih, T.-M., "Protection Against Nerve Agent-induced Neuropathology, but Not Cardiac Pathology, is Associated with the Anticonvulsant Action of Drug Treatment", Neurotoxicology Vol. 15, pp. 123-132, 1995.
  14. Capacio, B. R., Whalley, C. E., Byers, C. E., McDonough, J. H., "Intramuscular Diazepam Pharmacokinetics in Soman-Exposed Guinea Pigs", J. Appl. Toxicol., Vol. 21, pp. S67-S74. 2001. https://doi.org/10.1002/jat.813
  15. McDonough, J. H., McDonagle, J., Copeland, T., Zoeffel, D., Shih, T.-M., "Comparative Evaluation of Benzodiazepines for Control of Soman-induced Seizures", Arch. Toxicol., Vol. 73, pp. 473-478, 1999. https://doi.org/10.1007/s002040050637
  16. Solana, R. P., Harris, L. W., Carter, W. H., Talbot, B. G., Carchman, R. A., Gennings, C., "Evaluation of a Two Drug Combination Pretreatment Against Organophosphate Exposure", Toxicol. Appl. Pharmacol., Vol. 102, pp. 421-429, 1990. https://doi.org/10.1016/0041-008X(90)90038-V
  17. Jenner, A., Saleem, A., Swanston, D., "Transdermal Delivery of Physostigmine. A Pretreatment Against Organophosphate Poisoning", J. Pharm. Pharmacol., Vol. 47, pp. 206-212, 1994.
  18. 구자용, 김영우, 김인철, 남상우, 백두현, 서원준, "민군 겸용 Stigmine류 신경계 약물", 한국군사과학기술학회 2011년 종합학술대회 논문 초록집, p.207, 2011.
  19. Pope, C., Karanth, S., Liu, J., "Pharmacology and Toxicology of Cholinesterase Inhibitors", Environ. Toxicol. Pharmacol., Vol. 19, pp. 433-446, 2005. https://doi.org/10.1016/j.etap.2004.12.048
  20. Philippens, I. H. C. H. M., Wolthuis, O. L., Busker, R. W., Langenberg, J. P., Melchers, B. P. C., "Side Effects of Physostigmine as a Pretreatment in Guinea Pigs", Pharmacol. Biochem. Behav., Vol. 55, pp. 99-105, 1996. https://doi.org/10.1016/0091-3057(96)83115-7
  21. Myhrer, T., Enger, S., Aas, P., "Behavioral Side Effects in Rats Treated with Acetylcholinesterase Inhibitors Suggested Used as Prophylactics Against Nerve Agents", Pharm. Biochem. Behavior., Vol. 95(Issue 3), pp. 338-343, 2010. https://doi.org/10.1016/j.pbb.2010.02.010
  22. Myhrer, T., Enger, S., Aas, P., "Cognitive Side Effects in Rats Caused by Pharmacological Agents Used to Prevent Soman-Induced Lethality", Eur. J. Pharmacol., Vol. 483, pp. 271-279, 2004. https://doi.org/10.1016/j.ejphar.2003.09.041
  23. Choi, E.-K., Park, D., Yon, J.-M., Hur, G.-H., Ha, Y.-C., Che, J.-H., Kim, J., Shin, S., Jang, J. J., Hwang, S.-Y., Seong, Y.-H., Kim, D.J., Kim, J.-C., Kim, Y.-B., "Protection by Sustained Release of Physostigmine and Procyclidine of Soman Poisoning in Rats", Eur. J. Pharmacol., Vol. 505, pp. 83-91, 2004. https://doi.org/10.1016/j.ejphar.2004.10.034
  24. Lim, D. K., Ito, Y., Yu, Z. J., Hoskins, B., Ho, I. K., "Prevention of Soman Toxicity After the Continuous Administration of Physostigmine", Pharmacol. Biochem. Behav., Vol. 31, pp. 633- 639, 1988. https://doi.org/10.1016/0091-3057(88)90242-0
  25. Meshulam, Y., Davidovici, R., Wengier, A., Levy, A., "Prophylactic Transdermal Treatment with Physostigmine and Scopolamine Against Soman Intoxication in Guinea-Pigs", J. Appl. Toxicol., Vol. 15, pp. 263-266, 1995. https://doi.org/10.1002/jat.2550150406
  26. Philippens, I. H. C. H. M., Melchers, B. P. C., Oliver, B., Bruijnzeel, P. L. B., "Scopolamine Augments the Efficacy of Physostigmine Against Soman Poisoning in Guinea Pigs", Pharmacol. Biochem. Behav., Vol. 65, pp. 175-182, 2000. https://doi.org/10.1016/S0091-3057(99)00171-9
  27. Wetherell, J. R., "Continuous Administration of Low Dose Rates of Physostigmine and Hyoscine to Guinea-Pigs Prevents the Toxicity and Reduces the Incapacitation Produced by Soman Poisoning", J. Pharm. Pharmacol., Vol. 46, pp. 1023-1028, 1994. https://doi.org/10.1111/j.2042-7158.1994.tb03260.x
  28. Kim, Y.-B., Shin, S., Sok, D.-E., Kang, J.-K., "Effectiveness of Procyclidine in Combination with Carbamate Prophylactics Against Diisopropylfluorophosphate Poisoning", Environ. Toxicol. Pharmacol., Vol. 5, pp. 43-49, 1998. https://doi.org/10.1016/S1382-6689(97)10005-9
  29. Kim, Y.-B., Cheon, K.-C., Hur, G.-H., Phi, T.-S., Choi, S.-J., Hong, D.-S., Kang, J.-K., "Effect of Combinational Prophylactics Composed of Physostigmine and Procyclidine on Soman-induced Lethality, Seizures and Brain Injuries", Environ. Toxicol. Pharmacol., Vol. 11, pp. 15-21, 2002. https://doi.org/10.1016/S1382-6689(01)00096-5
  30. Haug, K. H., Myhrer, T., Fonnum, F., "The Combination of Donepezil and Procyclidine Protects Against Soman-Induced Seizures in Rats", Toxicol. Appl. Pharmacol., Vol. 220, pp. 156-163, 2007. https://doi.org/10.1016/j.taap.2006.12.023
  31. Weissman, B. A., Raveh, L., "Therapy Against Organophosphate Poisoning : The Importance of Anticholinergic Drugs with Antiglutamatergic Properties", Toxicol. Appl. Pharmacol., Vol. 232, pp. 351-358, 2008. https://doi.org/10.1016/j.taap.2008.07.005
  32. Kim, Y.-B., Phi, T.-S., Kim, W.-S., Cho, Y., Seo, W.-J., Choi, S.-J., Cheon, K.-C., Hur, G.-H., Yeon, G.-B., "Skin Irritation and Recrystallization Profiles of a Transdermal Patch Composed of Physostigmine and Procyclidine for the Prophylaxis of Organophosphate Poisoning", Korean J. Lab. Ani. Sci., Vol. 19, pp. 142-152, 2003.
  33. Kim, W.-S., Cho, Y., Kim, J.-C., Hang, Z.-Z., Park, S.-H., Choi, E.-K., Shin, S.-H., Nam, S.-Y., Kang, J.-K., Hwang, S.-Y., Kim, Y.-B., "Protection by a Transdermal Patch Containing Physostigmine and Procyclidine of Soman Poisoning in Dogs", Euro. J. Pharmacol., Vol. 21, pp. 135-142, 2005.
  34. LTS Lohmann Therapie-System AG(Germany), Prophylactic Transdermal Device Against Nerve Agents, White Paper, April, 2002.
  35. Philippens, I. H. C. H. M., Jongsma, M. J., Vanwersch, R. A. P., "NATO Advanced Research Workshop on Medical Treatment of Intoxication and Decontamination of Chemical Agents in the Area of Terrorist Attack. Efficacy of Prophylaxis and Treatment Against Soman Intoxication", Vol. 2006, pp. 113-122, 2006.
  36. DeMar, J. C., Clarkson, E. D., Ratcliffe, R. H., Campbell, A. J., Thangavelu, S. G., Herdman, C. A., Leader, H., Schulz, S. M., Marek, E., Medynets, M. A., Ku, T. C., Evans, S. A., Khan, F. A., Owens, R. R., Nambiar, M. P., Gordon, R. K., "Pro-2-PAM Therapy for Central and Peripheral Cholinesterases", Chem. Biol. Inter., Vol. 187, pp. 191-198, 2010. https://doi.org/10.1016/j.cbi.2010.02.015
  37. Caranto, G. R., Waibel, K. H., Asher, J. M., Larrison, R. W., Brechet, K. M., Schutz, M. B., Ravel, L., Ashani, Y., Wolfe, A. D., Maxwell, D. M., Doctor, B. P., "Amplification of the Effectiveness of Acetylcholinesterase for Detoxification of Organophosphorus Compounds by Bis-Quaterary Oximes", Biochem. Pharm., Vol. 47, pp. 347-357, 1994. https://doi.org/10.1016/0006-2952(94)90026-4
  38. Lundy, P. M., Hamilton, M. G., Sawyer, T. M., Mikler, J., "Comparative Protective Effects of HI-6 and MMB-4 Against Organophosphorus Nerve Agent Poisoning", Toxicology, Vol. 285, pp. 90- 96, 2011. https://doi.org/10.1016/j.tox.2011.04.006
  39. United States Army Medical Research Institute of Chemical Defense, Presented by Dr. Shih, T. M. 2002.
  40. Valiyaveettil, M., Alamneh, Y., Biggemann, L., Soojhawon, I., Docter, B. P., Nambiar, M. P., "Efficient Hydrolysis of the Chemical Warfare Nerve Agent Tabun by Recombinant and Purified Human and Rabbit Serum Paraoxonase 1", Biochem. Biophy. Res. Comm., Vol. 403, pp. 97-102, 2010. https://doi.org/10.1016/j.bbrc.2010.10.125
  41. Lenz., D. E., Clarkson, E. D., Cerasoli, D. M., "Butyrylcholinesterase as a Therapeutic Drug for Protection Against Percutaneous VX", Chem-Bio Inter. Vol. 185, pp. 249-252, 2010.
  42. Valiyaveettil., M., Alamneh, Y., Rezk, P., Biggemann, L., Perkins, M. W., Sciuto, A. M., Doctor, B. P., Nambiar, P., "Protective Efficacy of Catalytic Bioscavenger, Paraoxonase 1 Against Sarin and Soman Exposure in Guinea Pigs", Biochem. Pharm., Vol. 81, pp. 800-809, 2011. https://doi.org/10.1016/j.bcp.2010.12.024
  43. Saxena, A., Tipparaju, P., Luo, C., Doctor, B. P., "Pilot-Scale Production of Human Serum Butyrylcholinesterase Suitable for Use as a Bioscavanger Against Nerve Agent Toxicity", Proc. Biochem., Vol. 45, pp. 1313-1318, 2010. https://doi.org/10.1016/j.procbio.2010.04.021
  44. Kuca, K., Musilek, K., Jun, D., Bajgar, J., Kassa, J., "Handbook of Toxicology of Chemical Warfare Agents, Chapter 66 - Novel Oxime", pp. 997- 1021, 2009.
  45. Philippens, I. H. C. H. M., Physostigmine as a Pretreatment Against Organophosphate-Intoxication, Thesis University Utrecht, ISBN 90-393-1669-4, p. 13, 1998.