Malignant Hyperthermia: Evaluation of “Organon” 9426 in Malignant Hyperthermia Susceptible Pigs
Author(s)
Charles H. Williams
ABSTRACT
Control pigs required 109.9 ug/kg/min and MHS pigs required 72.4 ug/kg/min infusion of Organon 9426 to maintain a 90% block. It appears that Organon 9426 is only one-third to one-half as potent as Vecuronium in pigs. The fact that MHS pigs only require 66% of the infusion dose to maintain a 90% block suggests that there is difference in the neuromuscular effect of Organon 9426 in MHS vs. control pigs. A linear regression analysis of the dose response data to Organon 9426 in MHS pigs indicated that 427.033 ug/kg would be required to produce a 100% neuromuscular blockade vs. 586.31 ug/kg in control pigs. Nine of the ten MHS pigs did not develop MH or show any signs of impending MH during the halothane and succinylcholine challenge at the end of the infusion period. Organon 9426 is the first muscle relaxant to offer significant protective action at a clinical dose. This suggests that there is an allosteric site on the sodium channel (acetylcholine receptor) which regulates the flow of sodium ions through the sodium channel. Organon 9426 may be therapeutically effective in an active MH case [1].
Control pigs required 109.9 ug/kg/min and MHS pigs required 72.4 ug/kg/min infusion of Organon 9426 to maintain a 90% block. It appears that Organon 9426 is only one-third to one-half as potent as Vecuronium in pigs. The fact that MHS pigs only require 66% of the infusion dose to maintain a 90% block suggests that there is difference in the neuromuscular effect of Organon 9426 in MHS vs. control pigs. A linear regression analysis of the dose response data to Organon 9426 in MHS pigs indicated that 427.033 ug/kg would be required to produce a 100% neuromuscular blockade vs. 586.31 ug/kg in control pigs. Nine of the ten MHS pigs did not develop MH or show any signs of impending MH during the halothane and succinylcholine challenge at the end of the infusion period. Organon 9426 is the first muscle relaxant to offer significant protective action at a clinical dose. This suggests that there is an allosteric site on the sodium channel (acetylcholine receptor) which regulates the flow of sodium ions through the sodium channel. Organon 9426 may be therapeutically effective in an active MH case [1].
Cite this paper
Williams, C. (2015) Malignant Hyperthermia: Evaluation of “Organon” 9426 in Malignant Hyperthermia Susceptible Pigs. Open Journal of Molecular and Integrative Physiology, 5, 29-36. doi: 10.4236/ojmip.2015.52003.
Williams, C. (2015) Malignant Hyperthermia: Evaluation of “Organon” 9426 in Malignant Hyperthermia Susceptible Pigs. Open Journal of Molecular and Integrative Physiology, 5, 29-36. doi: 10.4236/ojmip.2015.52003.
References
[1] Williams, C.H. (2015) Malignant Hyperthermia: Organon 9426 Was Evaluated in 10 MHS Pigs and 8 Control Pigs. Presented at EB2015 Boston, 1 April 2015, as FASEBJ 29: Abstract W109, #1039.1. [2] Muir, A.W., Houston, J., Green, K.L., Marshall, R.J., Bowman, W.E. and Marshall, I.G. (1989) Effects of a New Neuromuscular Blocking Agent ORG-9426 in Anesthetized Cats and Pigs and in Isolated Nerve-Muscle Preparation. Brit J Physiol, 63, 400-410. [3] Mamabe, N., Nitta, S., Nagashima, H., Duncalf, D. and Foldes F.F. (1989) The in-Vivo Neuromuscular Effects of ORG-9426 in Rats and Guinea-Pigs. Anesthesiology, 71, A774. [4] Nagashima, H., Nguyen, H.D., Kinsey, A, Rosa, M., Hollinger, I., Goldiner, P.L. and Foldes, F.F. (1989) The Human Dose Response of ORG-9426. Anesthesiology, 71, A773. [5] Foldes, F.F., Chaudry, I., Goldiner, P.L. and Nagashima, H. (1989) The in-Vitro Neuromuscular Effects of ORG-9426 in Rodents. Anesthesiology, 71, A772. [6] Khuenl-Brady, K.S., Canfel, P.C., Miller, R.D., Castagnoli, K.P. and Agoston, S. (1989) Pharmacokinetics and Disposition of ORG-9616 and ORG-9426 in the Cat. Brit J Anaesth, 62, 225P-226P. [7] Buzello, W., Williams, C.H., Chandra, P., Watkins, M.L. and Dozier, S.E. (1985) Vecuronium and Porcine Malignant Hyperthermia. Anesthesia and Analgesia, 64, 515-519.
http://dx.doi.org/10.1213/00000539-198505000-00012 [8] Hoech Jr., G.P., Roberts, J.T., Williams, C.H., Waldman, S.D., Simpson, S.T., Trim, C.M. and Brazile, J. (1980) Prevention of Porcine Malignant Hyperthermia with Metocurine. In: Thermoregulatory Mechanisms and Their Therapeutic Implications, 4th International Symposium on the Pharmacology of Thermoregulation, Oxford1979, Karger, Basel, 137-141. [9] Williams, C.H., Dozier, S.E., Ilias, W.K. and Fulfer, R.T. (1984) Porcine Malignant Hyperthermia: Testing of Atracurium in MH Susceptible Pigs. Manuscript. [10] Buzello, W., Williams, C.H., Chandra, P. and Watkins, M.L. (1984) Preliminary Studies on the Response of Malignant Hyperthermia Pigs to Vecuronium. Intl. Anesth. Research Soc. 58th Congress Abstracts, 67. [11] Williams, C.H., Farias, M., Marvasti, M.A, Knight, A.B., Ekery, D.O., Daly, I.W. and Zayed, I. (1990) Malignant Hyperthermia Induction in Susceptible Swine Following Exposure to Arduan. IntI Anesth Research Soc 64th Congress, Honolulu, 10-14 March 1990. [12] Williams, C.H., Dozier, S.E., Ilias, W.K. and Fulfer, R.T. (1985) Porcine Malignant Hyperthermia: Testing of Atracurium in MH Susceptible Pigs. Anesthesia and Analgesia, 64, 112. [13] Williams, C.H., Hoech, G.P. and Zukaitis, M.G. (2014) A Review of the Factors Affecting the Incidence of Malignant Hyperthermia in the Greater Kansas City Area. Advances in Bioscience and Biotechnology, 5, 452-461.
http://dx.doi.org/10.4236/abb.2014.55055 [14] Williams, C.H., Dozier, S.E., Ilias, W.K., Fulfer, R.T., Zukaitis, M.G. and Hoech, G.P. Diltiazem and Malignant Hyperthermia. Submitted to Anesthesia and Analgesia. [15] Williams, C.H., Dozier, S.E. and Shanklin, M.D. (1986) Metabolic Rate in Malignant Hyperthermia Susceptible (MHS) Pigs. In: Tumbleson, M.E., Ed., Swine in Biomedical Research, Plenum, New York, 573-584. [16] Williams, C.H. (2014) Malignant Hyperthermia: A Runaway Thermogenic Futile Cycle at the Sodium Channel Level. Advances in Bioscience and Biotechnology, 5, 197-200.
http://dx.doi.org/10.4236/abb.2014.53025 [17] Williams, C.H. (2015) Malignant Hyperthermia: Organon 9426 Was Evaluated in 10 MHS Pigs and 8 Control Pigs. FASEB J, 29, 1.1039.1.
[1] Williams, C.H. (2015) Malignant Hyperthermia: Organon 9426 Was Evaluated in 10 MHS Pigs and 8 Control Pigs. Presented at EB2015 Boston, 1 April 2015, as FASEBJ 29: Abstract W109, #1039.1. [2] Muir, A.W., Houston, J., Green, K.L., Marshall, R.J., Bowman, W.E. and Marshall, I.G. (1989) Effects of a New Neuromuscular Blocking Agent ORG-9426 in Anesthetized Cats and Pigs and in Isolated Nerve-Muscle Preparation. Brit J Physiol, 63, 400-410. [3] Mamabe, N., Nitta, S., Nagashima, H., Duncalf, D. and Foldes F.F. (1989) The in-Vivo Neuromuscular Effects of ORG-9426 in Rats and Guinea-Pigs. Anesthesiology, 71, A774. [4] Nagashima, H., Nguyen, H.D., Kinsey, A, Rosa, M., Hollinger, I., Goldiner, P.L. and Foldes, F.F. (1989) The Human Dose Response of ORG-9426. Anesthesiology, 71, A773. [5] Foldes, F.F., Chaudry, I., Goldiner, P.L. and Nagashima, H. (1989) The in-Vitro Neuromuscular Effects of ORG-9426 in Rodents. Anesthesiology, 71, A772. [6] Khuenl-Brady, K.S., Canfel, P.C., Miller, R.D., Castagnoli, K.P. and Agoston, S. (1989) Pharmacokinetics and Disposition of ORG-9616 and ORG-9426 in the Cat. Brit J Anaesth, 62, 225P-226P. [7] Buzello, W., Williams, C.H., Chandra, P., Watkins, M.L. and Dozier, S.E. (1985) Vecuronium and Porcine Malignant Hyperthermia. Anesthesia and Analgesia, 64, 515-519.
http://dx.doi.org/10.1213/00000539-198505000-00012 [8] Hoech Jr., G.P., Roberts, J.T., Williams, C.H., Waldman, S.D., Simpson, S.T., Trim, C.M. and Brazile, J. (1980) Prevention of Porcine Malignant Hyperthermia with Metocurine. In: Thermoregulatory Mechanisms and Their Therapeutic Implications, 4th International Symposium on the Pharmacology of Thermoregulation, Oxford1979, Karger, Basel, 137-141. [9] Williams, C.H., Dozier, S.E., Ilias, W.K. and Fulfer, R.T. (1984) Porcine Malignant Hyperthermia: Testing of Atracurium in MH Susceptible Pigs. Manuscript. [10] Buzello, W., Williams, C.H., Chandra, P. and Watkins, M.L. (1984) Preliminary Studies on the Response of Malignant Hyperthermia Pigs to Vecuronium. Intl. Anesth. Research Soc. 58th Congress Abstracts, 67. [11] Williams, C.H., Farias, M., Marvasti, M.A, Knight, A.B., Ekery, D.O., Daly, I.W. and Zayed, I. (1990) Malignant Hyperthermia Induction in Susceptible Swine Following Exposure to Arduan. IntI Anesth Research Soc 64th Congress, Honolulu, 10-14 March 1990. [12] Williams, C.H., Dozier, S.E., Ilias, W.K. and Fulfer, R.T. (1985) Porcine Malignant Hyperthermia: Testing of Atracurium in MH Susceptible Pigs. Anesthesia and Analgesia, 64, 112. [13] Williams, C.H., Hoech, G.P. and Zukaitis, M.G. (2014) A Review of the Factors Affecting the Incidence of Malignant Hyperthermia in the Greater Kansas City Area. Advances in Bioscience and Biotechnology, 5, 452-461.
http://dx.doi.org/10.4236/abb.2014.55055 [14] Williams, C.H., Dozier, S.E., Ilias, W.K., Fulfer, R.T., Zukaitis, M.G. and Hoech, G.P. Diltiazem and Malignant Hyperthermia. Submitted to Anesthesia and Analgesia. [15] Williams, C.H., Dozier, S.E. and Shanklin, M.D. (1986) Metabolic Rate in Malignant Hyperthermia Susceptible (MHS) Pigs. In: Tumbleson, M.E., Ed., Swine in Biomedical Research, Plenum, New York, 573-584. [16] Williams, C.H. (2014) Malignant Hyperthermia: A Runaway Thermogenic Futile Cycle at the Sodium Channel Level. Advances in Bioscience and Biotechnology, 5, 197-200.
http://dx.doi.org/10.4236/abb.2014.53025 [17] Williams, C.H. (2015) Malignant Hyperthermia: Organon 9426 Was Evaluated in 10 MHS Pigs and 8 Control Pigs. FASEB J, 29, 1.1039.1.