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GOLDEN CHAIN TREE ( Laburnum anagyroides Medikus)

Medical Toxicology of Natural Substances, by Donald G. Barceloux, MDCopyright © 2008 John Wiley & Sons, Inc.

HISTORY

The toxicity of Laburnum seeds was recognized during the 19th century. 1 During this period, case reports asso-ciated convulsions and death with the ingestion of Laburnum seeds, but the validity of this association is unclear because of the lack of adequate data (e.g., post-mortem examination) to exclude other causes of death. 2 Studies during the early 1900s indicated that cytisine was the principal toxin in Laburnum species. 3 Ing identi-fi ed the chemical structure of cytisine in 1931. 4 Labur-num ingestion was a common occurrence in England during the late 1970s, primarily due to the attraction of children to the beautiful seeds and pods. During this period, the ingestion of parts from the golden chain tree accounted for an estimated 3,000 admissions to hospi-tals in England and Wales, but serious toxicity was not well documented. 5

BOTANICAL DESCRIPTION

British species of Laburnum include L. alpinum (Mill.)Bercht. & J.Presl (Scottish laburnum) and L. anagyroides.

Common Name: Golden Chain Tree Scientifi c Name: Laburnum anagyroides Medikus Botanical Family: Fabaceae (pea) Physical Description: This deciduous tree reaches up

to 12 – 30 ft ( ∼ 4 – 9 m) and has alternate leaves on a long stalk with three leafl ets. The golden, pea - like

fl owers appear in long drooping clusters during May and June. The green fruit is a long, fl attened pod that contains two to seven kidney - shaped seeds.

Distribution and Ecology: This beautiful fl owering tree is a native species in southern and central Europe that was introduced in the northern United States and southern Canada as an ornamental tree.

EXPOSURE

In the United States, Native Americans used Laburnum seeds as emetics and purgatives during rituals. Uses for alcoholic extracts of Laburnum species in traditional European medicine included the treatment of cough, constipation, respiratory depression, neuralgias, head-ache, asthma, and insomnia. In Europe during World War II, the leaves of Laburnum anagyroides were a substitute for tobacco. 6 In Eastern European countries, cytisine is currently an aid for smoking cessation. 7 However, the evidence for the effi cacy of cytisine for smoking cessation is inconclusive. 8 Most poisonings occur in children between July and September when the attractive pods and seeds appear. 9

PRINCIPAL TOXINS

Laburnum contains the toxic quinolizidine alkaloid, cytisine, which is structurally and pharmacologically similar to nicotine and lobeline. 3 The pK a of cytisine is 7.92. Laburnum seeds contain approximately 1%

Chapter 159

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890

cytisine by weight; the estimated lethal dose is approxi-mately 0.5 mg/kg. 10 Animal studies indicate that cytisine produces toxic effects similar to nicotine. 11 Figure 159.1 compares the chemical structures of cytisine and nico-tine. Cytisine is a nicotine agonist that binds to nicotinic receptors (e.g., α 4 β 2 ), 12 but the physiological and behav-ioral effects are complex, and cytisine is probably not active at all nicotine receptor subtypes. 13

DOSE RESPONSE

In a retrospective review of 49 children exposed to Laburnum seeds, the estimated ingestion of 1 – 10 seeds from L. anagyroides was not associated with serious toxicity. 14 Of the 49 children, 34 children remained asymptomatic. There are inadequate data to correlate the ingestion of a specifi c number of Laburnum seeds to toxic effects.

TOXICOKINETICS

In rodent studies, the average bioavailability of cytisine following a dose of 2 mg/kg body weight was 42% with peak blood concentrations occurring about 2 hours after ingestion. 15 About 18% of an oral dose of cytisine was excreted in the urine during the fi rst 24 hours after oral administration. The bile contained approximately 11% of the oral dose during the fi rst 6 hours. In animal studies, the plasma elimination of cytisine is relatively rapid (i.e., 1 – 3 hours), and limited biotransformation of cytisine occurs. 6

CLINICAL RESPONSE

Despite frequent exposures to Laburnum , particularly in children, there are few data on the clinical features of Laburnum (cytisine) intoxication. 16 Symptoms classi-cally associated with cytisine intoxication are similar to mild nicotine toxicity and the onset of symptoms usually begins about 1 / 2 – 4 hours after ingestion with nausea, vomiting, abdominal pain, pallor, lightheadedness, drowsiness, and ataxia. 17 Other clinical features include dilated pupils, tachycardia, delirium, paralysis, and respi-ratory depression. Symptoms resolve within 12 – 24

hours. An adult paranoid schizophrenic died suddenly at an inpatient facility without any obvious signs or symptoms of toxicity. 10 The death was associated with Laburnum toxicity because the autopsy demonstrated 23 Laburnum seedpods in the stomach. A comprehen-sive analysis of postmortem blood for drugs was not done. He had appeared in his usual state of health 10 minutes prior to death, and he did not display symptoms of cytisine toxicity immediately prior to death.

DIAGNOSTIC TESTING

Analytical methods for determination of cytisine in Laburnum extracts include reversed - phase high perfor-mance liquid chromatography, 18 gas chromatography/mass spectrometry, 19 liquid chromatography/atmo-spheric pressure chemical ionization/mass spectrometry, and liquid chromatography/electrospray ionization/tandem mass spectrometry. 20

TREATMENT

Management is supportive. Gut decontamination mea-sures are usually unnecessary, and there are no clinical data to determine the effi cacy of activated charcoal fol-lowing the Laburnum ingestion. Most children can be safely discharged after 4 – 6 hours of observation, provid-ing the child is asymptomatic and the vital signs are normal. There are no antidotes to cytisine toxicity.

References

1. Joll BB . On poisoning by Laburnum seeds . Br Med J 1879 ; 1 : 737 .

2. Usher Somers NL . Death from Laburnum poisoning . Lancet 1883 ; ii : 1114 .

3. Dale HH , Laidlaw PP . The physiological action of cytisine, the active alkaloid of laburnum ( Cytisus laburnum ) . J Pharmacol Exp Ther 1912 ; 3 : 205 – 221 .

4. Ing HR . Cytisine . Part I. J Chem Soc 1931 : 2195 – 2203 . 5. Forrester RM . Have you eaten laburnum? Lancet 1979 ; i :

1073 . 6. Tutka P , Zatonski W . Cytisine for the treatment of nicotine

addiction: from a molecule to therapeutic effi cacy . Phar-macol Rep 2005 ; 58 : 777 – 798 .

7. Etter J - F . Cytisine for smoking cessation a literature review and a meta - analysis . Arch Intern Med 2006 ; 166 : 1553 – 1559 .

8. Cahill K , Stead L , Lancaster T . Nicotine receptor partial agonists for smoking cessation . Cochrane Database Syst Rev 2007 ;( 1 ): CD006103 .

9. Mitchell RG . Laburnum poisoning in children. Report of 10 cases . Lancet 1951 ; 2 : 57 – 58 .

FIGURE 159.1. Chemical structures of cytisine and nicotine.

N

N H

O

N

N

CH3

Nicotine Cytisine

159 GOLDEN CHAIN TREE

891

10. Richards HG , Stephens A . A fatal case of laburnum seed poisoning . Med Sci Law 1970 ; 10 : 260 – 266 .

11. Barlow RB , McLeod LJ . Some studies on cytisine and its methylated derivatives . Br J Pharmacol 1969 ; 35 : 161 – 174 .

12. Zhang J , Steinbach JH . Cytisine binds with similar affi nity to nicotinic alpha 4 beta 2 receptors on the cell surface and in homogenates . Brain Res 2003 ; 959 : 98 – 102 .

13. Chandler CJ , Stolerman IP . Discriminative stimulus prop-erties of the nicotinic agonist cytisine . Psychopharmacol-ogy 1997 ; 129 ; 257 – 264 .

14. Bramley A , Goulding R . Laburnum “ poisoning. ” Br Med J 1981 ; 283 : 1220 – 1221 .

15. Kl ö cking H - P , Richter M , Damm G . Pharmacokinetic studies with 3 H - cytisine . Arch Toxicol 1980 ; 4 (Suppl): 312 – 314 .

16. Chin KC , Beattie TJ . Laburnum poisoning . Lancet 1979 ; i : 1299 .

17. Mitchell RG . Laburnum poisoning in children report of ten cases . Lancet 1951 ; ii : 57 – 58 .

18. Reavill C , Walther B , Stolerman IP , Testa B . Behavioural and pharmacokinetic studies on nicotine, cytisine and lobeline . Neuropharmacology 1990 ; 29 : 619 – 624 .

19. Nihei K , Shibata K , Kubo I . (+) - 2,3 - dehydro - 10 - oxo - alpha - isosparteine in Uresiphita reversalis larvae fed on Cytisus monspessulanus leaves . Phytochemistry 2002 ; 61 : 987 – 990 .

20. Beyer J , Peters FT , Kraemer T , Maurer HH . Detection and validated quantifi cation of toxic alkaloids in human blood plasma — comparison of LC - APCI - MS with LC - ESI - MS/MS . J Mass Spectrom 2007 ; 42 : 621 – 633 .