SOFT 2004 Meeting Abstracts - Society of Forensic Toxicologists

CIO
EFFECTS OF CHRONIC ACONITINE ADMINISTRATION ON ITS CONCENTRATION IN LIVER,
KIDNEY, HEART, AND BLOOD OF MICE
Kentaro Wada*, Makoto Nihira, Hideyuki Hayakawa, Yukari Tomita, Makiko Hayashida" Youkichi Ohno.
Department ofLegal Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo, JAPAN
Aims: Aconitum alkaloids are well known for their acute and high toxicity, for example, in the causation of severe
arrhythmias leading to death. Aconitine, one ofthe major Aconitum alkaloids, is a highly toxic compound from the Aconilum
species. The use ofAconitum alkaloids has been known since ancient times, over 2000 years in Asia as a homicidal agent,
sometimes as poison for arrowheads. Even today, aconites are sometimes used as homicidal or suicidal agents. Until today,
several cases of murder have been reported using single-dose ofa large amount ofAconitum alkaloids in Japan. In 1995, a
man murdered was subjected to autopsy in which Aconitum alkaloids were administered repeatedly over a period ofmonths,
in Saitama Prefecture, Japan. Although there are various studies reported on the single-dose effect ofaconitine, no reports are
available on the long-term effects of aconitine, probably due to its high toxicity. Therefore this study was conducted to
investigate the influence ofchronic administration ofaconitine in experimental animal models.
Methods: A total volume of 1.0 mg/kg/day was administered to the experimental animal models. The lethal dose 50%
(LD50) of aconitine for mice is 1.8 mg/kg (orally, single dose) and 0.308 mg/kg (intraperitoneally, single dose). The male
ICR (Institute ofCancer Research) mice were divided into 2 study groups: "acute group" (day 0: 0, 15,30,60,90, 120 min,
1440 min = 24 hours) and "chronic group" (days 1,3,7,1O,15,19,and 22), according to the time when the animals were
sacrificed. The experiments were conducted according to the guidelines of the Ethical Committee on Animal
Experimentation of Nippon Medical School (Tokyo, Japan). We determined the concentration of aconitine and its
metabolites (benzoylaconine and aconine) in organs and blood with gas chromatography/selected ion monitoring (GC/SIM).
In addition, we concurrently recorded the electrocardiogram (ECG).
Results: Fifteen min after administration on day 0, the early aconitine administered group (acute group) revealed peak organs
and blood concentration levels of aconitine with gradual decrease, thereafter. The concentration of aconitine in organs and
blood (from day 0 to day 22; 90 min after the last administration of aconitine) gradually decreased according to repeated
administration, whereas benzoylaconine and aconine increased. ECGrevealed various types of arrhythmias (for example,
ventricular fibrillation, ventricular tachycardia, torsade de pointes, atrioventricular block, and bundle branch block).
However, the frequency ofarrhythmias remarkably decreased with time and repeated administration of aconitine.
Conclusions: In this study, 2 facts were revealed. First, the frequencies offatal arrhythmias remarkably decreased to day 22.
Secondly, the organs and blood concentration of aconitine (90 min after the last administration of aconitine) gradually
decreased and its metabolites (benzoylaconine and aconine) increased until day 22. These 2 facts have raised the possibility
that the activity of drug metabolism increased due to long-term administration of aconitine. In the case of long-term
administration of aconitine, it is very important to determine not only the concentration ofaconitine but also its metabolites
(benzoylaconine and aconine) in the organs and blood from the viewpoint offorensic toxicology.
Keywords: aconitine; chronic administration; GC/SIM
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