Five Cases of Aconite Poisoning - Journal of Analytical Toxicology

Journal of Analytical Toxicology, Vol. 31, April 2007
Five Cases of Aconite Poisoning: Toxicokinetics
of Aconitines
Yuji Fujita 1,2, Katsutoshi Terui 3, Megumi Fujita 1,2, Atsushi Kakizaki 2, Norio Sato 3, Kohei Oikawa 3, Hidehiko AokP,
Katsuo TakahashP, and Shigeatsu Endo 3
1Poisoning and Drug Laboratory Division, Critical Care and Emergency Center, Iwate Medical University Hospital, 3-16-1
Honchoudori, Morioka, Iwate 020-0015, Japan; 2Department of Pharmacy, Iwate Medical University Hospital, 19-1 Uchirnaru,
Morioka, Iwate 020-8505, Japan; and 3Department of Emergency Medicine, Iwate Medical University School of Medicine,
19-1 Uchimaru, Morioka, Iwate 020-8505, Japan
Abstract
Aconite poisoning was examined in five patients (four males and
one female) aged 49 to 78 years old. The electrocardiogram
findings were as follows: ventricular tachycardia and ventricular
fibrillation in case 1, premature ventricular contraction and
accelerated idioventricular rhythm in case 2, AIVR in case 3, and
nonsustained ventricular tachycardia in cases 4 and 5. The patient
in case 1 was given percutaneous cardiopulmonary support
because of unstable hemodynamics, whereas the other patients
were treated with fluid replacement and antiarrhythmic agents.
The main aconitine alkaloid in each patient had a half-life that
ranged from 5.8 to 15.4 h over the five cases, and other detected
alkaloids had half-lives similar to the half-life of the main alkaloid
in each case. The half-life of the main alkaloid in case 1 was about
twice as long as the half-lives in the other cases, and high values
for the area under the blood concentration-time curve and the
mean residence time were only observed in case 1. These results
suggest that alkaloid toxicokinetics parameters may reflect the
severity of toxic symptoms in aconite poisoning.
Introduction
Aconite is a well-known toxic plant of the genus Aconitum
in the Ranunculaceae family. Aconite contains aconitine alkaloids
such as aconitines, benzoylaconines and aconines, and
the aconitines (aconitine, hypaconitine, jesaconitine, and
mesaconitine) are the causative agents of aconite poisoning,
since the toxicity of aconitines is much stronger than that of
other alkaloids (1). The LD50 value of aconitine in mice is reported
to be 1.8 mg/kg when given orally (1), and the lethal
dose of aconitine for humans is estimated to be 1-2 mg (2,3).
Most cases of aconite poisoning have occurred in Japan and
China. The common causes are ingestion of aconitine-containing
Chinese herbal medicine (4-7) and mistaken ingestion
of aconite instead of edible wild plants (8). Aconite has also
been used in cases of suicide and homicide because of its high
toxicity (9-11). Similar cases have been reported in Europe and
the United States, although aconite-poisoning cases are relatively
rare in these regions (12-14). Various toxic symptoms,
such as nausea, vomiting, numbness and palsy of the extremities,
and arrhythmia, are observed in aconite poisoning, with
arrhythmia being the most typical symptom. Aconite poisoning
often results in death due to cardiac arrest caused by a
fatal arrhythmia such as ventricular fibrillation (Vf), and therefore
an understanding of arrhythmias caused by aconite poisoning
is of importance.
There have been many pharmacological studies of aconitines
(1,15-21), and the toxicity of these molecules is known to be
due to their action on sodium channels in excitable
membranes (16-19). In contrast, the toxicokinetics of
aconitines in humans have only been examined in two reports:
a study of the distribution of aconitine alkaloids by Ito
et al. (22) and measurement of the half-life of aconitine by
Moritz et al. (14).
Establishment of pharmacokinetics (toxicokinetics) parameters
in aconite poisoning would be useful for improvement
of clinical treatment of poisoning cases. Such parameters
include half-life, area under the blood concentrationtime
curve (AUC), clearance (CL), volume of distribution,
and mean residence time (MRT). These parameters are typically
used in dosage regimen design: the half-life may be used to
determine the interval between doses, and CL can be used to
achieve a target AUC that is appropriate in terms of efficacy and
toxicity; CL is used, for example, in the formula-based calculation
of the dosage of the anticancer agent carboplatin (23).
We have developed a new method for rapid analysis of
aconitines in serum and urine, using liquid chromatography-mass
spectrometry (LC-MS) (24). The method was applied
to the determination of aconitines in serum collected
from five patients with aconite poisoning who were admitted
to the Critical Care and Emergency Center at Iwate Medical
University. In this paper, we report the toxicokinetics parameters
of aconitines calculated using serial serum concentrations
from the five patients.
1 32 Reproduction (photocopying) of editorial content of this journal is prohibited without publisher's permission.

Journal of Analytical Toxicology, Vol. 31, April 2007
Methods
Patients
A summary of background data for the five patients with
aconite poisoning is shown in Table I. The patients comprised
Table I. Profiles of Patients with Aconite Poisoning
Ingested
Height Weight Parts of
Case Age Gender (cm) (kg) Aconite ECG* Therapy
I 53 male 158 63 root VT DF
Vf PCPS
2 69 male 165 75 root PVC, AIVR fluid replacement
3 78 female - root AIVR fluid replacement
4 49 male 180 85 leaf NSVT fluid replacement,
antiarrhythmic
5 58 male 158 60 root NSVT fluid replacement,
antiarrhythmic
* Abbreviations: ECG, electrocardiogram; VT, ventricular tachycardia; DF, defibrillation; Vf, ventricular
fibrillation; PCPS, percutaneous cardiopulmonary support system; PVC, premature ventricular contraction;
AIVR, accelerated idioventricular rhythm; and NSVT, nonsustained ventricular tachycardia.
four males and one female, with ages ranging from 49 to 78
years old and a mean age (• standard deviation) of 61.4 + 11.9
years old. One of the patients had ingested aconite leaves and
four patients had eaten roots. The electrocardiogram findings
were as follows: ventricular tachycardia (VT) and Vf in patent
1, premature ventricular contraction (PVC)
and accelerated idioventricular rhythm (AIVR)
in patient 2, AIVR in patient 3, and non-sustained
ventricular tachycardia (NSVT) in pa-
tients 4 and 5. All the patients recovered from
the poisoning, with case 1 requiring additional
percutaneous cardiopulmonary support
(PCPS) because of unstable hemodynamics.
Reagents
Aconitine, mesaconitine, and hypaconitine
were purchased from Wako Pure Chemical
Industries (Osaka, Japan); jesaconitine
was purchased from Sanwa Shoyaku (Utsunomiya,
Japan); and methyllycaconitine
was purchased from Sigma-Aldrich (St. Louis,
MO) and used as an internal standard (I.S.).
Formic acid of high-performance liquid
chromatography (HPLC) grade and acetonitrile
of LC-MS grade were purchased from
100
~--- LS.
A
tO0.
.t--- LS.
C-1
A
5o
50
~/Jeuc~nittne
5
m,~616
m/z 632
................. m/'.t 646
L m/z 6"/6
m/z 683
, . . . . , ....
l0
, .... . ....
15
i .... , ....
20
, ....
Retention time (min)
..t
el
ae
~ ~m/Z 616
mlz 632
____,.._____,,.~J X I ~ .Iz646
._...7 L ,,I~ 676
O" ~ . . . . . . . . . mlz 683
5 tO 15 20
Retention time (min)
~.100
q LS. 100
B
~--- LS.
C-2
A~itine ~ 50
5
J / J vr4~(~ -/z 616
I ',. J\ I/ "~63:
I x.~ i L ........ ~'z646
/ L. m,~ a6
................................. ,,,'z ~ 0
10 15 20
Retention time (min)
5
Jmcmilme
....... ,t
10 15 20
Retention time (min)
Figure I. Selected ion-monitoring chromatograms of aconitines. Selected ions for aconitine: m/z 646; hypaconitine: m/z 616; jesaconitine: m/z 676; mesaconitine:
m/z 632; and methyllycaconitine (I.S.): m/z 683. Blank serum (A); spiked serum (I .0 nglmL) (B); patient sample (case I): 7 h after ingestion (C-I); and
patient sample (case I ): 62 h after ingestion (C-2).
m/Z 616
m/Z 632
m/Z 646
m/Z 6'16
m/Z 683
133

Journal of Analytical Toxicology, Vol. 31, April 2007
Kanto Kagaku (Tokyo, Japan). Other reagents were of
analytical reagent grade and were purchased from Wako Pure
Chemical Industries.
Sample preparation and equipment
One milliliter of serum was mixed with 2.5 ng of I.S. and 2 mL
of 0.025% (v/v) ammonia solution. The mixture was applied to
i
2
Case 1
3 i ..........................................
9 : Acxmitine
1
!o
-1
-2
-3
-4
3
i 2
1
134
!_l
g0
-2
~-3
[]
9 : J~itine
[] : Mesaconitine
1() 20 3~) 40 5() 60 70
Time after ingestion Cn)
Case2
r
r
: : Ae~nitine
Jes~emfine
: Mesaconifine
, r i
i
Cue 4
3 i ................................................................................................................................
9 : Aconitiae
1 9 : Jutine
o 2'o 3'0 5o 7o
Time after ingestion (h)
Cue5
~2 9 9 : Jeacceitine
[] : Memumitine
1
9 -
0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70
Time after ingestion (h)
Time after ingestion ~)
Case 3
9 : Aconithte
; Hypac~mtine
[] : Mesaconitine
O 10 20 30 40 50 60 70
Time after ingestion (11)
Figure 2. Logarithmic serum concentrations of aconitines after ingestion of aconite. The lines in
each graph indicate regression lines. A regression equation for each patient was obtained from
logarithmically transformed serum aconitine concentrations and time after ingestion. Case 1:
aconitine, y = -0.039x - 1.754 (R 2 = 0.992); jesaconitine, y = -0.045x + 0.216 (R 2 = 0.982).
Case 2: aconitine, y = -0.186x + 0.370 (R 2 = 0.999); jesaconitine, y = -0.119x + 1.848 (R 2 =
0.995); mesaconitine, y = -0.249x + 2.409 (R 2 = 0.998). Case 3: aconitine, y = -0.087x - 1.290
(R 2 = 0.984); mesaconitine, y = -0.120x - 0.037 (R 2 = 0.993). Case 4: jesaconitine, y = -0.106x
+ 0.429 (R 2 = 0.999). Case 5: aconitine, ,v= -0.086x - 1.552 (R 2 = 0.997); jesaconitine; y=
-0.085x + 0.747 (R 2 = 0.990).
an Extrelut NT3 column (Merck, Darmstadt, Germany) and the
column was left to stand for 15 min at room temperature.
Aconitines were then eluted with 15 mL of diethyl ether. The
eluate was evaporated to dryness under a stream of nitrogen gas
in a heat block at 40~ and dissolved in 0.2 mL of the mobile
phase. The serum samples were stored at --80~ and measurernents
were made within three days after sample collection.
LC was performed on a Waters 2690 in-
strument (Waters, Milford, MA). Separation
was achieved using an XTerra RP18 column
(150 x 2.l-ram i.d., 3.5-1Jm particle size, Waters)
protected by a guard column (10 x 2.lmm
i.d.) containing the same packing. The
injection volume was set to 20 IJL, and the
mobile phase was a mixture of 0.1% (v/v)
formic acid in acetonitrile and 0.1% (v/v)
formic acid in aqueous solution (24:76, v/v),
with a flow rate of 0.2 mL/min. The column
temperature was maintained at 40~
MS was performed on a Micromass ZMD
4000 instrument (Waters) operating in the
electrospray ionization positive ion mode. The
MS parameters were as follows: capillary potential,
3.0 kV; cone voltage, 60 V; ion source
temperature, 120~ drying gas temperature,
350~ and nitrogen gas flow rate, 350 L/h.
Measurements were carried out in the selected
ion monitoring mode, and the mass-tocharge
values of the monitoring ion were 646
for aconitine, 616 for hypaconitine, 676 for jesaconitine,
632 for mesaconitine, and 683 for
methyllycaconitine (I.S.). The monitoring ion
reflects the protonated alkaloid and formed
the main peak for each alkaloid. No interfering
endogenous substances were observed
in blank serum samples.
Toxicokinetics parameters of aconitines
Concentrations of serum aconitines were
plotted logarithmically against time after ingestion,
and a serum concentration-time
curve was obtained. The time of ingestion of
aconite is shown as 0 h, and the time after ingestion
was obtained from the patient or their
family. Regression analysis of these data was
performed for each patient, using at least
three concentration-time data points in the
terminal log-linear phase. The elimination
velocity constant (Kel) was calculated as Ke~ =
slope, where the slope is that of the regression
line. Serum half-lives for each alkaloid were
calculated using the following equation: halflife
= 0.693/Kel. AUC (from 0 to infinity) was
calculated using the logarithmic trapezoidal
method with extrapolation to infinity, and
MRT was calculated as MRT = AUMC/AUC,
where AUMC is the area under the moment
curve from 0 to infinity.

Journal of Analytical Toxicology, Vol. 31, April 2007
Results
Aconitine, jesaconitine, and mesaconitine were detected in
serum in cases 1, 2 and 5, and aconitine and jesaconitine were
found in case 4. Jesaconitine was the main alkaloid (that is, the
alkaloid with the highest serum concentration) in cases 1, 2, 4,
and 5. In case 3, the main alkaloid was mesaconitine, and hypaconitine
was detected only in case 3. Chrornatograms for
blank serum, spiked serum and a patient sample (case 1) are
shown in Figure 1. Logarithmic serum concentrations of
aconitines were plotted against time after ingestion for each
case (Figure 2). The log concentration-time curves showed
good linearity from 20 h after ingestion in case 1, from 8 h after
ingestion in case 2, from 6 h after ingestion in case 3, from 12
h after ingestion in case 4, and from 5 h after ingestion in case
5.
The toxicokinetics parameters for aconitines obtained from
the log concentration-time curves are shown in Table II. In case
1, the Kel values for aconitine and jesaconitine (the main alkaloid)
were 0.039 h -1 and 0.045 h -1, respectively, and the halflives
were 17.8 h and 15.4 h, respectively. In case 2, the Kel
values for aconitine, jesaconitine (the main alkaloid) and
mesaconitine were 0.186 h -1, 0.119 h -1, and 0.249 h -1, respectively,
and the half-lives were 3.7 h, 5.8 h, and 2.8 h, respectively.
In case 3, the Kel values for aconitine and mesaconitine
(the mainalkaloid) were 0.087 h -1 and 0.120 h -1, respectively,
and the half-lives were 8.0 h and 5.8 h, respectively. In case 4,
the Kel for jesaconitine (the main alkaloid) was 0.106 h -1, and
the half-life was 6.5 h. In case 5, the K~l values for aconitine and
jesaconitine (the main alkaloid) were 0.086 h -1 and 0.085 h -1,
and the half-lives were 8.1 h and 8.2 h, respectively.
In case 1, the AUCs for aconitine and jesaconitine (the main
alkaloid) were 5.1 ng.h/mL and 28.6 ng.h/mL, respectively,
and the MRTs were 23.6 h and 22.6 h, respectively. In case 2,
the AUCs for aconitine, jesaconitine (the main alkaloid) and
mesaconitine were 3.1 ng.h/mL, 33.5 ng.h/mL and 13.0
Table II. Toxicokinetics Parameters of Aconitines
I~i* Half- AUC
Case Aconitines (h ~ Life (h) (ng, h/mL) MET (h)
1 Aconitine 0.039 17.8 5.1 23.6
Jesaconitine* 0.045 15.4 28.6 22.6
2 Aconitine 0.186 3.7 3.1 10.8
Jesaconitine* 0.119 5.8 33.5 12.8
Mesaconitine 0.249 2.8 13.0 9.7
3 Aconitine 0.087 8.0 2.4 14.8
Mesaconitine t 0.120 5.8 5.4 11.9
4 Jesaconitine t 0.106 6.5 6.9 17.2
5 Aconitine 0.086 8.1 2.7 10.9
Jesaconitine t 0.085 8.2 26.1 11.5
* Abbreviations: Kel, elimination velocity constant; AUC, area under the blood
concentration-time curve; and MRT, mean residence time.
~" Main alkaloid: the alkaloid with the highest serum concentration among the
detected aconitines.
ng.h/mL, respectively, and the MRTs were 10.8 h, 12.8 h and 9.7
h, respectively. In case 3, the AUCs for aconitine and mesaconitine
(the main alkaloid) were 2.4 ng.h/mL and 5.4 ng.h/mL, respectively,
and the MRTs were 14.8 h and 11.9 h, respectively.
In case 4, the AUC for jesaconitine (the main alkaloid) was 6.9
ng.h/mL, and the MRT was 17.2 h. In case 5, the AUCs for
aconitine and jesaconitine (the main alkaloid) were 2.7
ng.h/mL and 26.1 ng.h/mL, respectively, and the MRTs were
10.9 h and 11.5 h, respectively.
Discussion
In this study, we determined toxicokinetics parameters (halflife,
AUC, MRT) for aconitines in five patients with aconite
poisoning. Ito et al. (22) have studied the distribution of aconitine
alkaloids in an autopsy case, and Moritz et al. (14) determined
the half-life of aconitine in a poisoning case, but the
current study is the first report of the toxicokinetics parameters
of aconitines in patients with aconite poisoning. The halflives
of the main alkaloid ranged from 5.8 to 15.4 h in the five
patients, and the half-lives of other detected alkaloids were
similar to the half-life of the main alkaloid in each case. The
half-life of hypaconitine was not calculated, but it is likely that
this value would have been similar to that of other alkaloids in
the same case because all aconitines detected in each case had
similar half-lives and aconitine alkaloids have closely related
molecular structures.
After a period of four times the half-life, 93.75% of the original
amount of an agent has been eliminated from the body.
Therefore, our results suggest that the main alkaloid is eliminated
from the body over a period of 23-62 h. However, it has
been reported that aconitines can be detected in urine until 7
days after ingestion, but that they are not detectable in serum
24 h after ingestion (10). Similarly, aconitines were detectable
in urine in our cases after they became undetectable in serum
(data not shown). Aconitines are distributed in high concentration
to the liver and kidney (22), and therefore it appears
that aconitines mainly migrate to the liver and kidney after absorption,
and are then eliminated gradually from the body.
The most important pathway appears to be via the kidney,
given the detection of high concentrations of aconitines in
urine (8,10) and the continuous detection of aconitines in
urine after intoxication (10). Therefore, deterioration in renal
function may lead to a delay in excretion of aconitines, and a
corresponding increase in half-life. Among our patients, the
half-life of the main alkaloid in case 1 was about 2 times longer
than those in the other cases, but the renal function of the patient
in case 1 was considered to be normal, since clinical data
for serum creatinine and blood urea nitrogen were in the
normal range. These results suggest that the prolonged half-life
in case 1 was not due to deterioration of renal function. However,
it is of note that cardiac output in case 1 was lower than
that in the other cases, due to hemodynamic instability, and the
patient required PCPS; therefore, the prolonged half-life in
case 1 may have been due to decreased cardiac output, rather
than to deterioration of renal function.
135

Journal of Analytical Toxicology, Vol. 31, April 2007
The AUC of the main alkaloid was larger in cases 1, 2, and 5
compared to cases 3 and 4, whereas the MRT of the main alkaloid
showed a tendency to prolong in cases 1 and 4 compared
with the other cases. Therefore, only case I showed high values
for both AUC and MRT. Because AUC reflects the amount of exposure
and MRT reflects the time of exposure, these results
suggest that a larger concentration of aconitines were acting
on sodium channels for a longer time in case 1, compared to
the other cases. In animal experiments, it has been reported
that the toxic symptoms in aconite poisoning are dependent on
the dose of aconitines (25), and our findings suggest that the
extent of toxic symptoms is affected not only by amount of exposure
to aconitines but also by time of exposure.
The AUC values in cases 3 and 4 were low compared with the
other cases. The patient in case 4 was the only one to ingest
leaves of the plant. The content of aconitine alkaloids varies according
to the part of the plant, growth region, season, and
species (26-33), and the content in roots is higher than that of
stems and leaves; the level of aconitines in roots was about 10
times that in stems (30), and about 300 times that in leaves
(29). Therefore, our results suggest that the AUC in case 4 reflects
the lower alkaloid content of leaves. The patient in case
3 had ingested roots, but the AUC in this patient was low compared
to other cases of root ingestion. Furthermore, in case 3
the main alkaloid differed from that in the other cases, and this
case was also the only one in which hypaconitine was detected
and in which jesaconitine was not detected. The levels of aconitine,
hypaconitine, jesaconitine, and mesaconitine in aconite
vary according to the part of plant, the growing region, the
aconite species, and the season (26-33); therefore our results
suggest that the alkaloid level and composition in case 3 was
influenced by one or more of these variables.
Overall, the calculated toxicokinetics parameters may give an
indication of the severity of toxic symptoms in aconite poisoning;
however, a mechanistic study and calculation of toxicokinetics
parameters in a larger numbers of patients are
needed for full establishment of the relationship between toxic
symptoms and toxicokinetics.
References
1. H. Sato, C. Yamada, C. Konno, Y. Ohizumi, K. Endo, and H.
Hikino. Pharmacological actions of aconitine alkaloids. Tohoku
J. Exp. Med. 128:175-187 (1979).
2. F.E. Camps. Gradwohl's Legal Medicine. John Wright & Sons,
Bristol, CT, 1968, p 674.
3. E. Rentoul and H. Smith. Glaister's Medical Jurisprudence and
Toxicology. Churchill Livingstone, Edinburgh, Scotland, 1973,
pp 520-521.
4. Y.T. Tai, RP.H. But, K. Young, and C.P. Lau. Cardiotoxicity after accidental
herb-induced aconite poisoning. Lancet 340" 1254-1256
(1992).
5. P. Dickens, Y.T. Tai, RP.H. But, B. Tomlinson, H.K. Ng, and K.W.
Yah. Fatal accidental aconitine poisoning following ingestion of
Chinese herbal medicine: a report of two cases. Forensic Sci. Int.
67:55-58 (1994).
6. RP.H. But, Y.T. Tai, and K. Young. Three fatal cases of herbal
aconite poisoning. Vet. Hum. Toxicol. 36:212-215 (1994).
7. C.C. Lin, T.Y.K. Chan, and J.F. Deng. Clinical features and man-
agement of herb-induced aconitine poisoning. Ann. Emerg. Med.
43' 574-579 (2004).
8. N. Yoshioka, K. Gonmori, A. Tagashira, O. Boonhooi, M.
Hayashi, Y. Saito, and M. Mizugaki. A case of aconitine poisoning
with analysis of aconitine alkaloids by GC/SIM. Forensic
Sci. Int. 81:117-123 (1996).
9. A. Mori, M. Mukaida, I. Ishiyama, J. Hori, Y. Okada, M. Sasaki, K.
Mii, and M. Mizugaki. Homicidal poisoning by aconite: report of
a case from the viewpoint of clinical forensic medicine. Jpn. ].
Legal Med. (Nippon Hoigaku Zasshi) 44:352-357 (1990) (in
Japanese, English abstract).
10. K. Kurasawa, H. Ohfusa, H. Matsuo, K. Matsuzawa, E. Kishi, K.
Matsubayashi, D. Maruyama, and M. Mizugaki. A case of "Torikabuto"
intoxication with documented follow-up measurements of
Aconitum alkaloids in the urine. Jpn. J. Toxicol. (Chudoku
Kenkyu) 6:185-188 (1993) (in Japanese, English abstract).
11. Y. Ohno. The experimental approach to the murder case of
aconite poisoning. J. Toxicol. Toxin. Rev. 17:1-11 (1998).
12. M. Imazio, R. Belli, F. Pomari, E. Cecchi, A. Chinaglia, G.
Gaschino, A. Ghisio, R. Trinchero, and A. Brusca. Malignant
ventricular arrhythmias due to Aconitum napellus seeds. Circulation
102:2907-2908 (2000)..
13. S.P. Elliott. A case of fatal poisoning with the aconite plant: quantitative
analysis in biological fluid. ScL Justice 42:111-115 (2002).
14. F. Moritz, P. Compagnon, I.G. Kaliszczak, Y. Kaliszczak, V.
Caliskan, and C. Girault. Severe acute poisoning with homemade
Aconitum napellus capsules: toxicokinetic and clinical
data. Clin. Toxicol. 43:873-876 (2005).
15. K. Peper and W. Trautwein. The effect of aconitine on the membrane
current in cardiac muscle. Pflugers Arch Gesamte Physiol
Menschen Tiere 296:328-336 (1967).
16. W.A. Catterall. Cooperative activation of action potential Na+
ionophore by neurotoxins. Proc. Natl. Acad. Sci. U.S.A. 72:
1782-1786 (1975).
17. W.A. Catterall. Neurotoxins as allosteric modifiers of voltagesensitive
sodium channels. Adv. Cytopharmacol. 3:305-316
(1979).
18. W.A. Catterall. Neurotoxins that act on voltage-sensitive sodium
channels in excitable membranes. Annu. Rev. Pharmacol. Toxicol.
20:15-43 (1980).
19. W.A. Catterall. Structure and function of voltage-sensitive ion
channels. Science 242:50-61 (1988).
20. J. Friese, J. Gleitz, U.T. Gutser, J.F. Heubach, T. Matthiesen, B. Wilffert,
and N. Selve. Aconitum sp. alkaloids: the modulation of
voltage-dependent Na+ channels, toxicity and antinociceptive
properties. Eur. J. Pharmacol. 337:165-174 (1997).
21. A. Ameri. The effects of Aconitum alkaloids on the central nervous
system. Prog. Neurobiol. 56:211-235 (1998).
22. K. Ito, S. Tanaka, M. Funayama, and M. Mizugaki. Distribution of
Aconitum alkaloids in body fluids and tissues in a suicidal case of
aconite ingestion. J. Anal. Toxicol. 24:348-353 (2000).
23. A.H. Calvert, D.R. Newell, L.A. Gumbrell, S. O'Reilly, M. Burnell,
F.E. Boxall, Z.H. Siddik, I.R. Judson, M.E. Gore, and E. Wiltshaw.
Carboplatin dosage: prospective evaluation of a simple formula
based on renal function. J. Clin. Oncol. 7:1748-1756 (1989).
24. Y. Fujita, M. Fujita, H. Niitsu, K. Oikawa, K. Terui, T. Akatsu, M.
Kikuchi, N. Sato, H. Aoki, K. Takahashi, and S. Endo. A simple
and rapid method for analysis of Aconitum alkaloids in serum and
urine using liquid chromatography electrospray ionization mass
spectrometry. J. Trad. Med. (Wakan lyakugaku Zasshi) 22:49-54
(2005).
25. S.D. Yakazu. Bibliographic studies on the intoxication of aconitine
root (Uzu, Bushi). Part I. Jpn. J. Orient. Med. (Nippon Toyo
Igaku Zasshi) 9:55-64 (1958) (in Japanese).
26. F. Kurosaki, T. Yatsunami, T. Okamoto, and Y. Ichinohe. Separation
and quantitative analysis of diterpene alkaloids in Japanese
Aconitum roots. Yakugaku Zasshi 98:1267-1273 (1978) (in
Japanese, English abstract).
27. M. Nakano and T. Yamagishi. Quantitative analysis of aconitine
136

Journal of Analytical Toxicology, Vol. 31, April 2007
alkaloids in "Bushi" and "Uzu", aconiti tuber, by high performance
liquid chromatography. Report of the Hokkaido Institute of
Public Health (Hokkaidoritsu Eisei Kenkyujoho), vol. 32, 1982, pp
21-26 (in Japanese, English abstract).
28. H. Hikino, S. Shiota, M. Takahashi, and M. Murakami. Seasonal
dynamics of the accumulation of aconitine alkaloids in Aconitum
carmichaeli roots. Shoyakugaku Zasshi 37:68-72 (1983)(in
Japanese, English abstract).
29. M. Mizugaki and K. Ito. A forensic toxicological study on
Aconitum alkaloids. Res. Pract. Forensic Med. (Hoigaku No Jissai
To Kenkyu) 44:1-16 (2001) (in Japanese, English abstract).
30. M. Ogata, T. Itou, H. Tuji, and Y. Kasahara. Qualitative and quantitative
analysis of aconitine analogs in Aconitum plants. Report
of the Yamagata Prefectural Institute of Public Health (Yamagataken
Eisei Kenkyujoho), vol. 36, 2003, pp 54-57 (in Japanese).
31. M. Taki, T. Matsuba, M. Fukuchi, M. Aburada, and M. Okada.
Comparison of seasonal variations on growth of Aconitum
carmichaeli DEBX. and constituents of root tubers cultivated in
Hokkaido and Ibaraki prefecture. Natural Medicines 58:55-63
(2004) (in Japanese, English abstract).
32. K. Okada and K. Kawaguchi. Change in chemical component
characters within and among years of aconite. Natural Medicines
59:36-41 (2005) (in Japanese, English abstract).
33. Z.H. Jiang, Y. Xie, H. Zhou, J.R. Wang, Z.Q. Liu, Y.F. Wong, X.
Cai, H.X. Xu, and L. Liu. Quantification of Aconitum alkaloids in
aconite roots by a modified RP-HPLC method. Phytochem. Anal.
16:415-421 (2005).
Manuscript received July 5, 2006;
revision received September 20, 2006.
137