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Pharmacokinetics and pharmacodynamics of the myotoxic venom of Pseudechis australis (mulga snake) in the anesthetised rat.
Clin Toxicol (Phila) 2014; 52(6):604-10CT

Abstract

CONTEXT

Myotoxicity is a common clinical effect of snake envenoming and results from either local or systemic myotoxins in snake venoms. Although numerous myotoxins have been isolated from snake venoms, there has been limited study on the relationship between the time course of venom concentrations (pharmacokinetics) and the time course of muscle injury measured as a rise in creatine kinase (CK) (pharmacodynamics).

OBJECTIVE

The aim of this study was to develop an in vivo model of myotoxicity to investigate the time course of myotoxicity and the effect of antivenom.

MATERIALS AND METHODS

Anesthetised rats were administered Pseudechis australis (mulga snake) venom either through i.v., i.m. or s.d. route, including a range of doses (5-100 μg/kg). Serial blood samples were collected for measurement of venom using enzyme immunoassay and measurement of CK and creatinine. Antivenom was administered before, 1 and 6 h after venom administration to investigate its effect on muscle injury. Plots of venom and CK versus time were made and the area under the curve (AUC) was calculated.

RESULTS

There was a significant dose-dependent increase in CK concentration after administration of P. australis venom, which was greatest for i.v. administration. Timed measurement of venom concentrations showed a rapid absorption through s.d. and i.m. routes and a delayed rise in CK concentrations following any route. Antivenom prevented myotoxicity shown by a decrease in the CK AUC, which was most effective if given earliest. There was a rise in creatinine following i.v. venom administration.

CONCLUSION

The study shows the delayed relationship between venom absorption and the rise in CK, consistent with the delayed onset of myotoxicity in human envenoming. Antivenom prevented myotoxicity more effectively if given earlier.

Authors+Show Affiliations

Department of Pharmacology, Monash Venom Group, Monash University , Victoria , Australia.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24940643

Citation

Hart, A J., et al. "Pharmacokinetics and Pharmacodynamics of the Myotoxic Venom of Pseudechis Australis (mulga Snake) in the Anesthetised Rat." Clinical Toxicology (Philadelphia, Pa.), vol. 52, no. 6, 2014, pp. 604-10.
Hart AJ, Hodgson WC, O'Leary M, et al. Pharmacokinetics and pharmacodynamics of the myotoxic venom of Pseudechis australis (mulga snake) in the anesthetised rat. Clin Toxicol (Phila). 2014;52(6):604-10.
Hart, A. J., Hodgson, W. C., O'Leary, M., & Isbister, G. K. (2014). Pharmacokinetics and pharmacodynamics of the myotoxic venom of Pseudechis australis (mulga snake) in the anesthetised rat. Clinical Toxicology (Philadelphia, Pa.), 52(6), pp. 604-10. doi:10.3109/15563650.2014.914526.
Hart AJ, et al. Pharmacokinetics and Pharmacodynamics of the Myotoxic Venom of Pseudechis Australis (mulga Snake) in the Anesthetised Rat. Clin Toxicol (Phila). 2014;52(6):604-10. PubMed PMID: 24940643.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics and pharmacodynamics of the myotoxic venom of Pseudechis australis (mulga snake) in the anesthetised rat. AU - Hart,A J, AU - Hodgson,W C, AU - O'Leary,M, AU - Isbister,G K, PY - 2014/6/19/entrez PY - 2014/6/19/pubmed PY - 2014/8/21/medline KW - Antivenom KW - Creatine kinase KW - Myotoxicity KW - Pharmacokinetics KW - Snake toxins KW - Venom SP - 604 EP - 10 JF - Clinical toxicology (Philadelphia, Pa.) JO - Clin Toxicol (Phila) VL - 52 IS - 6 N2 - CONTEXT: Myotoxicity is a common clinical effect of snake envenoming and results from either local or systemic myotoxins in snake venoms. Although numerous myotoxins have been isolated from snake venoms, there has been limited study on the relationship between the time course of venom concentrations (pharmacokinetics) and the time course of muscle injury measured as a rise in creatine kinase (CK) (pharmacodynamics). OBJECTIVE: The aim of this study was to develop an in vivo model of myotoxicity to investigate the time course of myotoxicity and the effect of antivenom. MATERIALS AND METHODS: Anesthetised rats were administered Pseudechis australis (mulga snake) venom either through i.v., i.m. or s.d. route, including a range of doses (5-100 μg/kg). Serial blood samples were collected for measurement of venom using enzyme immunoassay and measurement of CK and creatinine. Antivenom was administered before, 1 and 6 h after venom administration to investigate its effect on muscle injury. Plots of venom and CK versus time were made and the area under the curve (AUC) was calculated. RESULTS: There was a significant dose-dependent increase in CK concentration after administration of P. australis venom, which was greatest for i.v. administration. Timed measurement of venom concentrations showed a rapid absorption through s.d. and i.m. routes and a delayed rise in CK concentrations following any route. Antivenom prevented myotoxicity shown by a decrease in the CK AUC, which was most effective if given earliest. There was a rise in creatinine following i.v. venom administration. CONCLUSION: The study shows the delayed relationship between venom absorption and the rise in CK, consistent with the delayed onset of myotoxicity in human envenoming. Antivenom prevented myotoxicity more effectively if given earlier. SN - 1556-9519 UR - https://www.unboundmedicine.com/medline/citation/24940643/Pharmacokinetics_and_pharmacodynamics_of_the_myotoxic_venom_of_Pseudechis_australis__mulga_snake__in_the_anesthetised_rat_ L2 - http://www.tandfonline.com/doi/full/10.3109/15563650.2014.914526 DB - PRIME DP - Unbound Medicine ER -