Antivenom effect on lymphatic absorption and pharmacokinetics of coral snake venom using a large animal model

D. Paniagua, I. Vergara, R. Román, C. Romero, M. Benard-Valle, A. Calderón, L. Jiménez, Michael J Bernas, Marlys H Witte, Leslie V Boyer, A. Alagón

Research output: Contribution to journalArticle

Abstract

Context: Historically, administration and dosing of antivenom (AV) have been guided primarily by physician judgment because of incomplete understanding of the envenomation process. As demonstrated previously, lymphatic absorption plays a major role in the availability and pharmacokinetics (PK) of coral snake venom injected subcutaneously, which suggests that absorption from subcutaneous tissue is the limiting step for venom bioavailability, supporting the notion that the bite site is an ongoing venom depot. This feature may underlie the recurrence phenomena reported in viperid envenomation that appear to result from a mismatch between venom and AV PK. The role of lymphatic absorption in neutralization of venom by AV administered intravenously remains unclear. Methods: The effect of AV on systemic bioavailability and neutralization of Micrurus fulvius venom was assessed using a central lymph-cannulated sheep model. Venom was administered by subcutaneous injection in eight sheep, four with and four without thoracic duct cannulation and drainage. Two hours after venom injection, AV was administered intravenously. Venom and AV concentrations in serum and lymph were determined by ELISA assay from samples collected over a 6-h period and in tissues harvested post-mortem. Results: After AV injection, venom levels in serum fell immediately to undetectable with a subsequent increase in concentration attributable to non-toxic venom proteins. In lymph, AV became detectable 6 min after treatment; venom levels dropped concurrently but remained detectable 4 h later. Post-mortem samples from the venom injection site confirmed the presence of venom near the point of injection. Neither venom nor AV was detected at significant concentrations in major organs or contralateral skin. Conclusions: Intravenous AV immediately neutralizes venom in the bloodstream and can extravasate to neutralize venom absorbed by lymph but this neutralization seems to be slow and incomplete. Residual venom in the inoculation site demonstrates that this site functions as a depot where it is not neutralized by AV, which allows the venom to remain active with slow delivery to the bloodstream for ongoing systemic distribution.

Original languageEnglish (US)
Pages (from-to)727-734
Number of pages8
JournalClinical Toxicology
Volume57
Issue number8
DOIs
StatePublished - Aug 3 2019

Fingerprint

Antivenins
Elapidae
Snake Venoms
Pharmacokinetics
Venoms
Animals
Animal Models
Lymph
Injections
Biological Availability
Sheep
Tissue
Thoracic Duct

Keywords

  • coral snake
  • Equine F(ab´)2 antivenom
  • lymphatic absorption
  • neutralization
  • pharmacokinetics
  • thoracic duct
  • venom depot

ASJC Scopus subject areas

  • Toxicology

Cite this

Paniagua, D., Vergara, I., Román, R., Romero, C., Benard-Valle, M., Calderón, A., ... Alagón, A. (2019). Antivenom effect on lymphatic absorption and pharmacokinetics of coral snake venom using a large animal model. Clinical Toxicology, 57(8), 727-734. https://doi.org/10.1080/15563650.2018.1550199

Antivenom effect on lymphatic absorption and pharmacokinetics of coral snake venom using a large animal model. / Paniagua, D.; Vergara, I.; Román, R.; Romero, C.; Benard-Valle, M.; Calderón, A.; Jiménez, L.; Bernas, Michael J; Witte, Marlys H; Boyer, Leslie V; Alagón, A.

In: Clinical Toxicology, Vol. 57, No. 8, 03.08.2019, p. 727-734.

Research output: Contribution to journalArticle

Paniagua, D, Vergara, I, Román, R, Romero, C, Benard-Valle, M, Calderón, A, Jiménez, L, Bernas, MJ, Witte, MH, Boyer, LV & Alagón, A 2019, 'Antivenom effect on lymphatic absorption and pharmacokinetics of coral snake venom using a large animal model', Clinical Toxicology, vol. 57, no. 8, pp. 727-734. https://doi.org/10.1080/15563650.2018.1550199
Paniagua, D. ; Vergara, I. ; Román, R. ; Romero, C. ; Benard-Valle, M. ; Calderón, A. ; Jiménez, L. ; Bernas, Michael J ; Witte, Marlys H ; Boyer, Leslie V ; Alagón, A. / Antivenom effect on lymphatic absorption and pharmacokinetics of coral snake venom using a large animal model. In: Clinical Toxicology. 2019 ; Vol. 57, No. 8. pp. 727-734.
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abstract = "Context: Historically, administration and dosing of antivenom (AV) have been guided primarily by physician judgment because of incomplete understanding of the envenomation process. As demonstrated previously, lymphatic absorption plays a major role in the availability and pharmacokinetics (PK) of coral snake venom injected subcutaneously, which suggests that absorption from subcutaneous tissue is the limiting step for venom bioavailability, supporting the notion that the bite site is an ongoing venom depot. This feature may underlie the recurrence phenomena reported in viperid envenomation that appear to result from a mismatch between venom and AV PK. The role of lymphatic absorption in neutralization of venom by AV administered intravenously remains unclear. Methods: The effect of AV on systemic bioavailability and neutralization of Micrurus fulvius venom was assessed using a central lymph-cannulated sheep model. Venom was administered by subcutaneous injection in eight sheep, four with and four without thoracic duct cannulation and drainage. Two hours after venom injection, AV was administered intravenously. Venom and AV concentrations in serum and lymph were determined by ELISA assay from samples collected over a 6-h period and in tissues harvested post-mortem. Results: After AV injection, venom levels in serum fell immediately to undetectable with a subsequent increase in concentration attributable to non-toxic venom proteins. In lymph, AV became detectable 6 min after treatment; venom levels dropped concurrently but remained detectable 4 h later. Post-mortem samples from the venom injection site confirmed the presence of venom near the point of injection. Neither venom nor AV was detected at significant concentrations in major organs or contralateral skin. Conclusions: Intravenous AV immediately neutralizes venom in the bloodstream and can extravasate to neutralize venom absorbed by lymph but this neutralization seems to be slow and incomplete. Residual venom in the inoculation site demonstrates that this site functions as a depot where it is not neutralized by AV, which allows the venom to remain active with slow delivery to the bloodstream for ongoing systemic distribution.",
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AU - Vergara, I.

AU - Román, R.

AU - Romero, C.

AU - Benard-Valle, M.

AU - Calderón, A.

AU - Jiménez, L.

AU - Bernas, Michael J

AU - Witte, Marlys H

AU - Boyer, Leslie V

AU - Alagón, A.

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N2 - Context: Historically, administration and dosing of antivenom (AV) have been guided primarily by physician judgment because of incomplete understanding of the envenomation process. As demonstrated previously, lymphatic absorption plays a major role in the availability and pharmacokinetics (PK) of coral snake venom injected subcutaneously, which suggests that absorption from subcutaneous tissue is the limiting step for venom bioavailability, supporting the notion that the bite site is an ongoing venom depot. This feature may underlie the recurrence phenomena reported in viperid envenomation that appear to result from a mismatch between venom and AV PK. The role of lymphatic absorption in neutralization of venom by AV administered intravenously remains unclear. Methods: The effect of AV on systemic bioavailability and neutralization of Micrurus fulvius venom was assessed using a central lymph-cannulated sheep model. Venom was administered by subcutaneous injection in eight sheep, four with and four without thoracic duct cannulation and drainage. Two hours after venom injection, AV was administered intravenously. Venom and AV concentrations in serum and lymph were determined by ELISA assay from samples collected over a 6-h period and in tissues harvested post-mortem. Results: After AV injection, venom levels in serum fell immediately to undetectable with a subsequent increase in concentration attributable to non-toxic venom proteins. In lymph, AV became detectable 6 min after treatment; venom levels dropped concurrently but remained detectable 4 h later. Post-mortem samples from the venom injection site confirmed the presence of venom near the point of injection. Neither venom nor AV was detected at significant concentrations in major organs or contralateral skin. Conclusions: Intravenous AV immediately neutralizes venom in the bloodstream and can extravasate to neutralize venom absorbed by lymph but this neutralization seems to be slow and incomplete. Residual venom in the inoculation site demonstrates that this site functions as a depot where it is not neutralized by AV, which allows the venom to remain active with slow delivery to the bloodstream for ongoing systemic distribution.

AB - Context: Historically, administration and dosing of antivenom (AV) have been guided primarily by physician judgment because of incomplete understanding of the envenomation process. As demonstrated previously, lymphatic absorption plays a major role in the availability and pharmacokinetics (PK) of coral snake venom injected subcutaneously, which suggests that absorption from subcutaneous tissue is the limiting step for venom bioavailability, supporting the notion that the bite site is an ongoing venom depot. This feature may underlie the recurrence phenomena reported in viperid envenomation that appear to result from a mismatch between venom and AV PK. The role of lymphatic absorption in neutralization of venom by AV administered intravenously remains unclear. Methods: The effect of AV on systemic bioavailability and neutralization of Micrurus fulvius venom was assessed using a central lymph-cannulated sheep model. Venom was administered by subcutaneous injection in eight sheep, four with and four without thoracic duct cannulation and drainage. Two hours after venom injection, AV was administered intravenously. Venom and AV concentrations in serum and lymph were determined by ELISA assay from samples collected over a 6-h period and in tissues harvested post-mortem. Results: After AV injection, venom levels in serum fell immediately to undetectable with a subsequent increase in concentration attributable to non-toxic venom proteins. In lymph, AV became detectable 6 min after treatment; venom levels dropped concurrently but remained detectable 4 h later. Post-mortem samples from the venom injection site confirmed the presence of venom near the point of injection. Neither venom nor AV was detected at significant concentrations in major organs or contralateral skin. Conclusions: Intravenous AV immediately neutralizes venom in the bloodstream and can extravasate to neutralize venom absorbed by lymph but this neutralization seems to be slow and incomplete. Residual venom in the inoculation site demonstrates that this site functions as a depot where it is not neutralized by AV, which allows the venom to remain active with slow delivery to the bloodstream for ongoing systemic distribution.

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KW - Equine F(ab´)2 antivenom

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KW - neutralization

KW - pharmacokinetics

KW - thoracic duct

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