Serum elimination profiles of methyllycaconitine and deltaline in cattle following oral administration of larkspur (Delphinium barbeyi)

Benedict T. Green USDA Agricultural Research Service, Poisonous Plant Research Laboratory, 1150 E 1400 N, Logan, UT 84341.

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Kevin D. Welch USDA Agricultural Research Service, Poisonous Plant Research Laboratory, 1150 E 1400 N, Logan, UT 84341.

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Dale R. Gardner USDA Agricultural Research Service, Poisonous Plant Research Laboratory, 1150 E 1400 N, Logan, UT 84341.

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Bryan L. Stegelmeier USDA Agricultural Research Service, Poisonous Plant Research Laboratory, 1150 E 1400 N, Logan, UT 84341.

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T. Zane Davis USDA Agricultural Research Service, Poisonous Plant Research Laboratory, 1150 E 1400 N, Logan, UT 84341.

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Daniel Cook USDA Agricultural Research Service, Poisonous Plant Research Laboratory, 1150 E 1400 N, Logan, UT 84341.

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Stephen T. Lee USDA Agricultural Research Service, Poisonous Plant Research Laboratory, 1150 E 1400 N, Logan, UT 84341.

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James A. Pfister USDA Agricultural Research Service, Poisonous Plant Research Laboratory, 1150 E 1400 N, Logan, UT 84341.

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Kip E. Panter USDA Agricultural Research Service, Poisonous Plant Research Laboratory, 1150 E 1400 N, Logan, UT 84341.

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Abstract

Objective—To describe the simple elimination kinetics of methyllycaconitine (MLA) and deltaline and evaluate the heart rate response in cattle following oral administration of larkspur.

Animals—5 healthy Angus steers that were habituated to metabolism crates.

Procedures—Tall larkspur (Delphinium barbeyi) in the early flowering stage was collected, dried, and ground. Each steer received a single dose of larkspur that was equivalent to 10.4 mg of MLA/kg and 11.0 mg of deltaline/kg via oral administration. Steers were housed in metabolism crates during a 96-hour period following larkspur administration; heart rate was monitored continuously, and blood samples were collected periodically for analysis of serum MLA and deltaline concentrations as well as assessment of pharmacokinetic parameters.

Results—No overt clinical signs of poisoning developed in any steer during the experiment. Mean ± SE heart rate reached a maximum of 79.0 ± 5.0 beats/min at 17 hours after larkspur administration. Serum MLA concentration was correlated directly with heart rate. Mean times to maximal serum concentration of MLA and deltaline were 8.8 ± 1.2 hours and 5.0 ± 0.6 hours, respectively. Mean elimination half-life values for MLA and deltaline were 20.5 ± 4.1 hours and 8.2 ± 0.6 hours, respectively.

Conclusions and Clinical Relevance—Following larkspur administration in 5 healthy steers, maximum serum concentrations of MLA and deltaline were detected within 10 hours, and changes in serum MLA concentration and heart rate were correlated. Results indicated that cattle that have consumed larkspur will eliminate 99% of MLA and deltaline from serum within 144 hours.

Abstract

Objective—To describe the simple elimination kinetics of methyllycaconitine (MLA) and deltaline and evaluate the heart rate response in cattle following oral administration of larkspur.

Animals—5 healthy Angus steers that were habituated to metabolism crates.

Procedures—Tall larkspur (Delphinium barbeyi) in the early flowering stage was collected, dried, and ground. Each steer received a single dose of larkspur that was equivalent to 10.4 mg of MLA/kg and 11.0 mg of deltaline/kg via oral administration. Steers were housed in metabolism crates during a 96-hour period following larkspur administration; heart rate was monitored continuously, and blood samples were collected periodically for analysis of serum MLA and deltaline concentrations as well as assessment of pharmacokinetic parameters.

Results—No overt clinical signs of poisoning developed in any steer during the experiment. Mean ± SE heart rate reached a maximum of 79.0 ± 5.0 beats/min at 17 hours after larkspur administration. Serum MLA concentration was correlated directly with heart rate. Mean times to maximal serum concentration of MLA and deltaline were 8.8 ± 1.2 hours and 5.0 ± 0.6 hours, respectively. Mean elimination half-life values for MLA and deltaline were 20.5 ± 4.1 hours and 8.2 ± 0.6 hours, respectively.

Conclusions and Clinical Relevance—Following larkspur administration in 5 healthy steers, maximum serum concentrations of MLA and deltaline were detected within 10 hours, and changes in serum MLA concentration and heart rate were correlated. Results indicated that cattle that have consumed larkspur will eliminate 99% of MLA and deltaline from serum within 144 hours.

  • 1.

    Nation PN, Benn MH, Roth SH, et al. Clinical signs and studies of the site of action of purified larkspur alkaloid, methyllycaconitine, administered parenterally to calves. Can Vet J 1982;23:264266.

    • Search Google Scholar
    • Export Citation
  • 2.

    Olsen JD, Manners GD. Toxicology of diterpenoid alkaloids in rangeland larkspur (Delphinium spp.). In: Cheeke PR. Toxicants of plant origin: alkaloids. Vol I. Boca Raton, Fla: CRC Press, 1989;291326.

    • Search Google Scholar
    • Export Citation
  • 3.

    Green BT, Pfister JA, Cook D, et al. Effects of larkspur (Delphinium barbeyi) on heart rate and electrically evoked electromyographic response of the external anal sphincter in cattle. Am J Vet Res 2009;70:539546.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Olsen JD, Manners GD, Pelletier SW. Poisonous properties of larkspur (Delphinium spp.). Collectanea Bot (Barc) 1990;19:141151.

  • 5.

    Manners GD, Panter KE, Ralphs MH, et al. Toxicity and chemical phenology of norditerpenoid alkaloids in the tall larkspurs (Delphinium species). J Agric Food Chem 1993;41:96100.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Manners GD, Panter KE, Pelletier SW. Structure-activity relationships of norditerpenoid alkaloids occurring in toxic larkspur (Delphinium) species. J Nat Prod 1995;58:863869.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Gardner DR, Manners GD, Ralphs MH, et al. Quantitative analysis of norditerpenoid alkaloids in larkspur (Delphinium spp.) by Fourier transform infrared spectroscopy. Phytochem Anal 1997;8:5562.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Ralphs MH, Gardner DR, Turner DL, et al. Predicting toxicity of tall larkspur (Delphinium barbeyi): measurement of the variation in alkaloid concentration among plants and among years. J Chem Ecol 2002;28:23272341.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Pfister JA, Gardner DR, Panter KE, et al. Larkspur (Delphinium spp.) poisoning in livestock. J Nat Toxins 1999;8:8194.

  • 10.

    Turek JW, Kang CH, Campbell JE, et al. A sensitive technique for the detection of the alpha 7 neuronal nicotinic acetylcholine receptor antagonist, methyllycaconitine, in rat plasma and brain. J Neurosci Methods 1995;61:113118.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Panter KE, Manners GD, Stegelmeier BL, et al. Larkspur poisoning: toxicology and alkaloid structure-activity relationships. Biochem Syst Ecol 2002;30:113128.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Stegelmeier BL, Hall JO, Gardner DR, et al. The toxicity and kinetics of larkspur alkaloid, methyllycaconitine, in mice. J Anim Sci 2003;81:12371241.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Welch KD, Panter KE, Gardner DR, et al. The effect of 7,8-methylenedioxylycoctonine-type diterpenoid alkaloids on the toxicity of methyllycaconitine in mice. J Anim Sci 2008;86:27612770.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Gardner DR, Panter KE, Pfister JA, et al. Analysis of toxic norditerpenoid alkaloids in Delphinium species by electrospray, atmospheric pressure chemical ionization, and sequential tandem mass spectrometry. J Agric Food Chem 1999;47:50495058.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Chen W, Nemoto T, Kobayashi T, et al. ECG and heart rate determination in fetal cattle using a digital signal processing method. Anim Sci J 2002;73:545551.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Ward JM, Cockcroft VB, Lunt GG, et al. Methyllycaconitine: a selective probe for neuronal alpha-bungarotoxin binding sites. FEBS Lett 1990;270:4548.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Alkondon M, Pereira EF, Wonnacott S, et al. Blockade of nicotinic currents in hippocampal neurons defines methyllycaconitine as a potent and specific receptor antagonist. Mol Pharm 1992;41:802808.

    • Search Google Scholar
    • Export Citation
  • 18.

    López MG, Montiel C, Herrero CJ, et al. Unmasking the functions of the chromaffin cell alpha7 nicotinic receptor by using short pulses of acetylcholine and selective blockers. Proc Natl Acad Sci U S A 1998;24:1418414189.

    • Search Google Scholar
    • Export Citation
  • 19.

    Dobelis P, Madl JE, Pfister JA, et al. Effects of Delphinium alkaloids on neuromuscular transmission. J Pharmacol Exp Ther 1999;291:538546.

    • Search Google Scholar
    • Export Citation
  • 20.

    Pfister JA, Panter KE, Manners GD, et al. Reversal of tall larkspur (Delphinium barbeyi) poisoning in cattle with physostigmine. Vet Hum Toxicol 1994;36:511514.

    • Search Google Scholar
    • Export Citation
  • 21.

    Pfister JA, Panter KE, Manners GD. Effective dose in cattle of toxic alkaloids from tall larkspur (Delphinium barbeyi). Vet Hum Toxicol 1994;36:1011.

    • Search Google Scholar
    • Export Citation
  • 22.

    Shargel L, Yu ABC. Pharmacokinetics of drug absorption. In: Applied biopharmaceutics and pharmacokinetics. 3rd ed. Stamford, Conn: Appleton & Lange, 1993;177179.

    • Search Google Scholar
    • Export Citation
  • 23.

    Stegelmeier BL, Panter KE, Pfister JA, et al. Experimental modification of larkspur (Delphinium spp.) poisoning in livestock. In: Garland TR, Barr AC, eds. Toxic plants and other natural toxicants. Wallingford, England: CAB International, 1998;205210.

    • Search Google Scholar
    • Export Citation
  • 24.

    Macallan DR, Lunt GG, Wonnacott S, et al. Methyllycaconitine and (+)-anatoxin-a differentiate between nicotinic receptors in vertebrate and invertebrate nervous systems. FEBS Lett 1988;226:357363.

    • Crossref
    • Search Google Scholar
    • Export Citation

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