Abstract
Lycorine is the main alkaloid of many Amaryllidaceae and known to cause poisoning with still unknown mechanisms. Longer lasting toxicological core symptoms of nausea and emesis may become a burden for human and animal patients and may result in substantial loss of water and electrolytes. To optimise the only empirical symptomatic antiemetic drug treatment at present, it is important to elucidate the causative involved targets of lycorine-induced emesis. Therefore, in the current study, we have tested the actions of a various antiemetic drugs with selective receptor affinities on lycorine-induced nausea and emesis in vivo in dogs. Beagle dogs were pre-treated in a saline vehicle-controlled crossover and random design with diphenhydramine, maropitant, metoclopramide, ondansetron or scopolamine prior lycorine administration (2 mg/kg subcutaneously). In vivo effects were assessed by a scoring system for nausea and emesis as well as by the number and lag time of emetic events for at least 3 h. Moreover, plasma pharmacokinetic analysis was carried out for ondansetron before and after lycorine injection. The data show that histaminergic (H1), muscarinic and dopaminergic (D2) receptors are presumably not involved in lycorine-induced emetic effects. While ondansetron significantly reduced the number of emetic events, lycorine-induced emesis was completely blocked by maropitant. Only ondansetron also significantly decreased the level of nausea and was able to prolong the lag time until onset of emesis suggesting a preferential participation of 5-HT3 receptors in lycorine-induced nausea. Thus, it is the first in vivo report evidencing that predominantly neurokinin-1 (NK1) and to a lesser extent 5-hydroxytryptamine 3 (5-HT3) receptors are involved in lycorine-induced emesis facilitating a target-oriented therapy.
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References
Beleslin DB, Stefanović-Denić K, Samardžić R (1986) Comparative behavioural effects of anticholinergic agents in cats: psychomotor stimulation and aggression. Pharmacol Biochem Behav 24:581–586
Bonner TI (1989) New subtypes of muscarinic acetylcholine receptors. Trends Pharmacol Sci 10(Suppl):11–15
Campbell A (2000) Daffodil. In: Campbell A, Chapman M (eds) Handbook of poisoning in cats and dogs. Blackwell, Oxford, pp 116–118
De la Puente-Redondo VA, Tilt N, Rowan TG, Clemence RG (2007) Efficacy of maropitant for treatment and prevention of emesis caused by intravenous infusion of cisplatin in dogs. Am J Vet Res 68:48–56
Fennell CW, Van Staden J (2001) Crinum species in traditional and modern medicine. J Ethnopharmacol 78:15–26
Food and Drug Administration (2007) Freedom of information summary. NADA, Silver Spring, MD, pp 141–263
Frohne D, Pfänder HJ (2004) Amaryllidaceae. In: Frohne D, Pfänder HJ (eds) Giftpflanzen. Ein Handbuch für Apotheker, Ärzte, Toxikologen und Biologen, 5th edn. Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, pp 33–35
Golding JF, Stott JRR (1997) Comparison of the effects of a selective muscarinic receptor antagonist and hyoscine (scopolamine) on motion sickness, skin conductance and heart rate. Br J Clin Pharmacol 43:633–637
Horn CC (2007) Is there a need to identify new anti-emetic drugs? Drug Discov Today Ther Strateg 4:183–187
Jaspersen-Schib R (1970) Toxische Amaryllidaceae. Pharm Acta Helv 45:424–433
Jordan K, Schmoll HJ, Aapro MS (2007) Comparative activity of antiemetic drugs. Crit Rev Oncol Hematol 61:162–175
Junko I, Akiko T, Yumiko K, Noiyoshi O (1994) Poisoning by lycoris radiata plants. Pharm Mon (Gekkan Yakuji) 36:855–857
Kamimura H (2006) Genetic polymorphism of cytochrome P450s in beagles: possible influence of CYP1A2 deficiency on toxicological evaluations. Arch Toxicol 80:732–738
King GL (1990) Animal models in the study of vomiting. Can J Physiol Pharmacol 68:260–268
Klinkenberg I, Blokland A (2010) The validity of scopolamine as a pharmacological model for cognitive impairment: a review of animal behavioral studies. Neurosci Biobehav Rev 34:1307–1350
Krenzelok EP, Mrvos R, Jacobsen TD (2002) Contrary to the literature, vomiting is not a common manifestation associated with plant exposures. Vet Hum Toxicol 44:298–300
Kretzing S, Abraham G, Seiwert B, Ungemach FR, Krügel U, Regenthal R (2011) Dose-dependent emetic effects of the amaryllidaceous alkaloid lycorine in beagle dogs. Toxicon 57:117–124
Larson EW, Pfenning MA, Richelson E (1991) Selectivity of antimuscarinic compounds for muscarinic receptors of human brain and heart. Psychopharmacology (Berl) 102:162–165
LeGrand SB, Walsh D (2010) Scopolamine for cancer-related nausea and vomiting. J Pain Symptom Manag 40:136–141
McNulty J, Nair JJ, Bastida J, Pandey S, Griffin C (2009) Structure-activity studies on the lycorine pharmacophore: a potent inducer of apoptosis in human leukaemia cells. Phytochemistry 70:913–919
Morishima K (1897) Chemische und pharmakologische Untersuchungen über die Alkaloide der Lycoris radiata Herb. Arch Exp Path Pharmacol 40:221–240
Mrvos R, Krenzlok EP, Jacobsen TD (2001) Toxidromes associated with the most common plant ingestions. Vet Hum Toxicol 43:366–369
Percie du Sert N, Rudd JA, Moss R, Andrews PL (2009) The delayed phase of cisplatin-induced emesis is mediated by the area postrema and not the abdominal visceral innervation in the ferret. Neurosci Lett 465(1):16–20
Plumb DC (2008) Plumb’s veterinary drug handbook, 6th edn. Ames, Iowa
Sanger GJ, Andrews PLR (2001) Emesis. In: Farthing MJG, Ballinger AB (eds) Drug therapy for gastrointestinal and liver disease. Martin Dunitz Ltd, London, pp 45–61
Sanger GJ, Andrews PLR (2006) Treatment of nausea and vomiting: gaps in our knowledge. Auton Neurosci 129:3–16
Schinkel AH, Wagenaar E, Mol CA, van Deemter L (1996) P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 97:2517–2524
Scuderi PE (2003) Pharmacology of antiemetics. Int Anesthesiol Clin 41:41–66
Simpson KH, Murphy P, Colthup PV, Whelan P (1992) Concentration of ondansetron in cerebrospinal fluid following oral dosing volunteers. Psychopharmacology 109:497–498
Takahashi T, Kurosawa S, Whiley JW, Owyang C (1991) Mechanism for the gastrokinetic action of domperidone. In vitro studies in guinea pigs. Gastroenterology 101:703–710
Ungemach FR (2006) Scopolamin. In: Löscher W, Ungemach FR, Kroker R (eds) Pharmakotherapie bei Haus- und Nutztieren, 8th edn. Enke, Stuttgart, p 213
Webster CRL (2005) Clinical pharmacology. Quick look series in veterinarian medicine. Teton NewMedia, Jackson
Yamamoto C, Murakami H, Koyabu N, Takanaga H, Matsuo H, Uchiumi T, Kuwano M, Naito M, Tsuruo T, Ohtani H, Sawada Y (2002) Contribution of P-glycoprotein to efflux of ramosetron, a 5-HT3 receptor antagonist, across the blood-brain barrier. J Pharm Pharmacol 54:1055–1063
Yang SH, Suh JH, Lee MG (2010) Pharmacokinetic interaction between tamoxifen and ondansetron in rats: non-competetive (hepatic) ans competitive (intestinal) inhibition of tamoxifen metabolism by ondansetron via CYP2D subfamiliy and 3A1/2. Cancer Chemother Pharmacol 65:407–418
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The authors gratefully acknowledge the skilful technical assistance of Ina Hochheim, Katja Sommer and Ingrid Lorenz.
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Kretzing, S., Abraham, G., Seiwert, B. et al. In vivo assessment of antiemetic drugs and mechanism of lycorine-induced nausea and emesis. Arch Toxicol 85, 1565–1573 (2011). https://doi.org/10.1007/s00204-011-0719-9
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DOI: https://doi.org/10.1007/s00204-011-0719-9