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Five Cases of Aconite Poisoning: Toxicokinetics of Aconitines
Abstract and Figures
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.
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... Assuming a time to peak plasma concentration (Tmax) of 1 hour and an elimination half-life of 3-4 hours, the aconitine concentration in serum most probably reached the maximum concentration after administration (Cmax) of at least 8 ng/mL during the first hour after intake [9]. Lower concentrations have been associated with toxic effects on the cardiovascular, nervous, and gastrointestinal system in other case reports [9,17,18]. In most reported deaths from aconitine poisoning, aconitine concentrations in blood have exceeded 10 ng/mL, although concentrations as low as 3.6 ng/mL may be considered lethal unless treated [19]. ...
... In aconitine poisoning, concentrations have been reported to be considerably higher in urine than in blood [17,18], which was also the case in our patient. This suggests that aconitine is detectable for a longer time after intake in urine than in blood and underlines the importance of securing both blood and urine samples from the patient, especially if the possibility of aconitine poisoning comes to mind after the acute symptomatic period has passed. ...
Background
We report a case of a clinical challenge lasting for 12 months, with severe and unresolved clinical features involving several medical disciplines.
Case presentation
A 53-year-old Caucasian male, who had been previously healthy apart from a moderate renal impairment, was hospitalized 12 times during a 1-year period for a recurrent complex of neurological, cardiovascular, and gastrointestinal symptoms and signs, without any apparent etiology. On two occasions, he suffered a cardiac arrest and was successfully resuscitated. Following the first cardiac arrest, a cardiac defibrillator was inserted. During the 12th admission to our hospital, aconitine poisoning was suspected after a comprehensive multidisciplinary evaluation and confirmed by serum and urine analyses. Later, aconitine was also detected in a hair segment, indicating exposure within the symptomatic period. After the diagnosis was made, no further episodes occurred. His cardiac defibrillator was later removed, and he returned to work. A former diagnosis of epilepsy was also abandoned. Criminal intent was suspected, and his wife was sentenced to 11 years in prison for attempted murder. To make standardized assessments of the probability for aconitine poisoning as the cause of the eleven prior admissions, an “aconitine score” was established. The score is based on neurological, cardiovascular, gastrointestinal, and other clinical features reported in the literature. We also make a case for the use of hair analysis to confirm suspected poisoning cases evaluated after the resolution of clinical features.
Conclusion
This report illustrates the medical challenge raised by cases of covert poisoning. In patients presenting with symptoms and signs from several organ systems without apparent cause, poisoning should always be suspected. To solve such cases, insight into the effects of specific toxic agents is needed. We present an “aconitine score” that may be useful in cases of suspected aconitine poisoning.
... h [8]. Moritz F et al. [9] reported that a man's plasma aconitine level decreased to 0.02 ng/ml from 1.75 ng/mL 12 hours after treatment. Most postmortem detected samples were collected from victims who had not undergone treatment, and the relevant toxicology data of aconitine in victims who have received long-term treatment in previous clinical and forensic practice are lacking. ...
Aconitum species are commonly used in traditional Chinese medicine, and they have a narrow therapy window due to the possibility of aconitine poisoning. Aconitine poisoning deaths appear infrequently in forensic practice. It is important to collect valuable body samples in time due to the rapid absorption and excretion of aconitine. However, it is unknown whether postmortem samples have value for toxicological analysis if the deceased has experienced long-term treatment before death. Herein, we present a case of a woman who died after 12 days of failed active treatment for aconitine poisoning. Aconitine was detected in the liver tissue. To our knowledge, this is the first case report describing the detection of aconitine in a decedent after long-term active treatment. The findings indicated that the aconitine concentration in liver tissue can be maintained after long-term treatment; this information may therefore serve as a reference in forensic practice.
... 6 Fujita Y et.al have reported the lower alkaloid content of leaves as compared to roots in their study. 5 While aconites are rarely used in modern medicine due to its toxicity, it is still being used as a traditional as well as a culinary herb in homeopathy to decrease fever, painful joints, as cardiac depressant, to treat neuralgia and also applied as in liniments as rubifacient for external application. In Nepal, people often use it as a health supplement to enhance appetite. ...
Aconite is the well-known toxic plant as well as valuable drug since decades. Most of the intoxications are accidental whereas suicidal attempt is rather rare after ingestion. This case report is about three persons who landed in our emergency department after consuming Aconite accidentally as an herbal medicine. Two of them were managed immediately while one was declared dead on arrival.
... Whether it is oral ingestion or dermal contact, absorption of aconitine occurs rapidly within a few minutes (Stork & Marraffa, 2005). The half-maximal lethal dose (LD50) of aconitine in mice is 1.8 mg/kg via oral ingestion, while in humans, it is about 1-2 mg (Fujita et al., 2007;Sato et al., 1979). This chapter discusses A. napellus L. in depth, including taxonomy and distribution, ethnopharmacology, phytochemistry, reported biological properties, and associated toxicities. ...
Background
Radix Aconiti Lateralis (Fuzi), a mono‐herbal preparation of Aconitum herbs in the genus Aconitum , is commonly used in traditional Chinese medicine (TCM) to treat critical illnesses. The curative effect of Fuzi is remarkable. However, the toxic effects of Fuzi are still a key clinical focus, and the substances inducing nephrotoxicity are still unclear. Therefore, this study proposes a research model combining “ in vitro and in vivo component mining‐virtual multi‐target screening‐active component prediction‐literature verification” to screen potential nephrotoxic substances rapidly.
Method
The UHPLC‐Q‐Exactive‐Orbitrap MS analysis method was used for the correlation analysis of Fuzi's in vitro–in vivo chemical substance groups. On this basis, the key targets of nephrotoxicity were screened by combining online disease databases and a protein–protein interaction ( PPI ) network. The computer screening technique was used to verify the binding mode and affinity of Fuzi's components with nephrotoxic targets. Finally, the potential material basis of Fuzi‐induced nephrotoxicity was screened.
Results
Eighty‐one Fuzi components were identified. Among them, 35 components were absorbed into the blood. Based on the network biology method, 21 important chemical components and three potential key targets were screened. Computer virtual screening revealed that mesaconine, benzoylaconine, aconitine, deoxyaconitine, hypaconitine, benzoylhypaconine, benzoylmesaconine, and hypaconitine may be potential nephrotoxic substances of Fuzi.
Conclusions
Fuzi may interact with multiple components and targets in the process of inducing nephrotoxicity. In the future, experiments can be designed to explore further. This study provides a reference for screening Fuzi nephrotoxic components and has certain significance for the safe use of Fuzi.
Aconite poisoning refers to toxicity resulting from plants belonging to the Aconitum genus, which comprises over 350 different species of perennial flowering plants that grow in temperate mountainous areas of the northern hemisphere (North America, Europe, Asia). These plants contain a group of toxins known as aconite alkaloids, which encompass numerous closely related toxic compounds. Conventional teaching from toxicology textbooks has broadly classified these alkaloids based on their mechanism of action, often simplifying them as substances that prevent sodium channel inactivation. However, this is an oversimplified and sometimes inaccurate description, as some aconite alkaloids can act as sodium channel blockers. Aconite alkaloids have a long history of use as poisonous substances and have been historically employed for hunting, assassinations, traditional medicine, and self-inflicted harm. Toxicity can occur due to the consumption of traditional medicines derived from aconitum plants or the ingestion of aconite plants and their derivatives. The clinical manifestations of aconite poisoning may encompass gastrointestinal symptoms, sensory alterations, seizures, and life-threatening dysrhythmias that may not respond to standard treatments. Treatment is primarily supportive however evaluation and management of these patients should be personalized and carried out in collaboration with a toxicologist.
Compounds from plants that are used in traditional medicine may have medicinal properties. It is well known that plants belonging to the genus Aconitum are highly poisonous. Utilizing substances derived from Aconitum sp. has been linked to deadly negative effects. In addition to their toxicity, the natural substances derived from Aconitum species may have a range of biological effects on humans, such as analgesic, anti-inflammatory, and anti-cancer characteristics. Multiple in silico, in vitro, and in vivo studies have demonstrated the effectiveness of their therapeutic effects. In this review, the clinical effects of natural compounds extracted from Aconitum sp., focusing on aconite-like alkaloids, are investigated particularly by bioinformatics tools such as the quantitative structure-activity relationship method, molecular docking, and predicted pharmacokinetic and pharmacodynamic profiles. The experimental and bioinformatics aspects of aconitine's pharmacogenomic profile are discussed. Our review could help shed light on the molecular mechanisms of Aconitum sp. compounds. The effects of several aconite-like alkaloids such as aconitine, methyllycacintine, or hypaconitine on specific molecular targets, including voltage-gated sodium channels, CAMK2A and CAMK2G during anaesthesia, or BCL2, BCL-XP, and PARP-1 receptors during cancer therapy, are evaluated. According to the reviewed literature, aconite and aconite derivatives have a high affinity for the PARP-1 receptor. The toxicity estimations for aconitine indicate hepatotoxicity and hERG II inhibitor activity; however, this compound is not predicted to be AMES toxic or a hERG I inhibitor. The efficacy of aconitine and its derivatives in treating many illnesses has been proven experimentally. Toxicity occurs as a result of the large ingested dose; however, a valuable component of the usage of this drug in future research is based on the small quantity of an active compound that fulfils a therapeutic role.
Background:
Extracorporeal cardiopulmonary resuscitation (ECPR) represents last-line salvage therapy for poisoning-induced cardiac arrest but no review has focused on this specific area.
Objective:
This scoping review sought to evaluate the survival outcomes and characteristics of published cases of ECPR for toxicological arrest, with the aim of highlighting the potential and limitations of ECPR in toxicology.Eligibility Criteria.We searched PubMed and Cochrane for eligible papers from database inception to October 1, 2022 using the keywords "toxicology", "ECLS" and "CPR". References of included publications were searched to identify additional relevant articles. Qualitative synthesis was used to summarize the evidence.
Results:
85 articles were chosen: 15 case series, 58 individual cases and 12 other publications that were analyzed separately due to ambiguity. ECPR may improve survival outcomes in selected poisoned patients, although the extent of benefit is unclear. As ECPR for poisoning-induced arrest may have better prognosis compared to from other aetiologies, it is likely reasonable to apply ELSO ECPR consensus guideline recommendations to toxicological arrest.Out-of-hospital cardiac arrest alone may not be sufficient grounds to deny ECPR if effective resuscitation had been promptly instituted. Poisonings involving membrane-stabilizing agents and cardio-depressive drugs, and cardiac arrests with shockable rhythms appear to have better outcomes. ECPR may permit excellent neurologically-intact recovery despite prolonged low-flow time of up to four hours. Early ECLS activation and pre-emptive catheter placement can significantly shorten time-to-ECPR and possibly improve survival.
Conclusion:
As effects of poisoning may be reversible, ECPR can potentially support poisoned patients through the critical peri-arrest state.
A highly functionalized BCDE model ring system of aconitine has been synthesized for the first time via a strategy involving oxidative dearomatization/IMDA, Wagner–Meerwein rearrangement, Michael addition and reductive cyclization.
A simple and rapid method for determination of Aconitum alkaloids, aconitine, mesaconitine, hypaconitine and jesaconitine, in serum and urine samples has been developed using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) combined with Extrelut® column extraction. The protonated molecular ions were observed as base peaks of these alkaloids. The alkaloids were separated on an XTerra® RP18 column with isocratic elution with a solvent mixture of 0.1% (v/v) formic acid in acetonitrile and 0.1% (v/v) formic acid in aqueous solution (24:76, v/v) using selective ion monitoring of protonated molecular ions. The calibration curves of the alkaloids in serum and urine were linear in the range of 5-200 pg per injection, and the detection limits of the alkaloids were 1 pg per injection (S/N=3). The recovery rates of the alkaloids ranged from 83.7% to 89.0% in serum and from 85.6% to 89.9% in urine. The inter-day precision and intra-day precision were acceptable. This method of analysis can be used for identification and quantitative determination of Aconitum alkaloids in cases of aconite poisoning and will be useful for investigating the pharmacokinetics of aconite substances in humans. In addition, it is simple and rapid and should therefore be useful in emergency medicine, in which quick and accurate test results are required. © 2005, Medical and Pharmaceutical Society for WAKAN-YAKU. All rights reserved.
Study objective: We define the potential sources, clinical manifestations, and treatment of aconitine poisoning. Methods: The database of the National Poison Center in Taiwan was retrospectively searched for the diagnosis of aconitine poisoning for 1990 to 1999. The reasons for taking the aconite roots, the clinical features, management, and possible predisposing factors were noted. Results: A total of 17 cases occurred and consisted of 9 men and 8 women aged 30 to 70 years. Thirteen patients ingested aconite roots as treatment for rheumatism and wounds. Two patients volunteered to test the effects of aconite roots in a drug study. Two patients accidentally ingested the aconite roots. After a latent period of 10 to 90 minutes, patients developed a combination of neurologic (n=17), cardiovascular (n=14), gastrointestinal (n=9), and other (n=5) features typical of aconitine poisoning. Four patients developed ventricular tachycardia. All patients received supportive treatment. Patients with ventricular tachycardia were also treated with charcoal hemoperfusion. All patients made a complete recovery. Conclusion: Life-threatening ventricular tachycardia can occur after the consumption of aconite roots. The risk is higher with inadequately processed aconite roots, large doses, or tincture preparations. With increasing popularity of herbal medicines, herb-induced aconitine poisoning may also be seen in Western countries.
The increase rate of mother tuberous root weight of Aconite did not changed from year to year. The total alkaloid and aconitine alkaloid contents increased from planting to spring of the next year and decreased toward autumn. The number of child roots increased rapidly from June-July and reached the peak in the middle of August. The total weight of child roots increased all through the growing period. It seemed that the total alkaloid and aconitine alkaloid contents did not steadily increase but rather fluctuated. No significant differences were observed for chemical components among the years studied.
Aconitum carmichaeli plants were cultivated in Hokkaido and Ibaraki from 1992 to 1993; the growth of the plants and the content of aconitine alkaloids, total-alkaloid, sucrose, starch and trans-aconitic acid in the root tubers were compared on each harvest time. Shoot emergence from soil in Hokkaido and Ibaraki was observed in May and March and the time of flowering in Hokkaido and Ibaraki was in September and August. The plant height and dry weight of aerial parts and daughter tubers reached the maxima in September. These growth indexes in Ibaraki were markedly superior to those in Hokkaido. In both cultivated fields, all the alkaloid contents in mother tubers decreased rapidly, but mesaconitine and aconitine content in daughter tubers increased gradually during the bolting and flowering periods. In September, these aconitine alkaloid contents in daughter tubers in Ibaraki were higher than those in Hokkaido. In October, the alkaloid contents in the tubers in Hokkaido were almost equal to those in Ibaraki, but sucrose content in Hokkaido was higher than that in Ibaraki. It is important for the cultivation of Aconitum carmichaeli plants to judge proper harvest time from seasonal variations in the dry weights and the content of aconitine alkaloids in daughter tubers.
Preparations of Aconitum roots are employed in Chinese and Japanese medicine for analgesic, antirheumatic and neurological indications. The recent surge in use of phytomedicine derived from traditional Chinese medicine as well as increasing concerns about possible toxic effects of these compounds have inspired a great deal of research into the mechanisms by which certain Aconitum alkaloids may act on the central nervous system. The pharmacological effects of preparations of Aconitum roots are attributed to several diterpenoid alkaloids. The main alkaloid of these plants is aconitine, a highly toxic diterpenoid alkaloid which is known to suppress the inactivation of voltage-dependent Na+ channels by binding to neurotoxin binding site 2 of the alpha-subunit of the channel protein. In this article the pharmacology of several structurally related Aconitum alkaloids is highlighted and their therapeutic vs toxic potential is discussed. Neurochemical and neurophysiological studies will be reviewed with emphasis on the effects of the alkaloids in regions of the brain that have been implicated in pain transmission and generation of epileptic activity. Considering the chemical structure of the Aconitum alkaloids as well as their mechanism of action, a subdivision in three groups becomes obvious: the first group comprises such alkaloids which possess high toxicity due to two ester boundings at the diterpene skeleton. The members of this group activate voltage-dependent sodium channels already at resting potential and inhibit noradrenaline reuptake. Activation of sodium channels and in consequence excessive depolarization with final inexcitability and suppression of pain transmission account for their antinociceptive properties. The second group comprises less toxic monoesters which have been shown to possess strong antinociceptive, antiarrhythmic and antiepileptiform properties due to a blockade of the voltage-dependent sodium channel. Electrophysiological studies have revealed a use-dependent inhibition of neuronal activity by these alkaloids. They seem to be competitive antagonists of the group I-alkaloids. The third group of Aconitum alkaloids are lacking an ester side chain in the molecule. Toxicity is markedly reduced when compared with the two other groups. They fail to affect neuronal activity, but are reported to have antiarrhythmic actions suggesting that they may have different affinities to various subtypes of the alpha-subunit of the Na+ channel in brain and heart.
Abstract Aconites (wolfsbane) are the plants in the genus Aconitum (the Ranunculaceae family), containing highly toxic alkaloids such as aconitine, mesaconitine. hypaconitine, and jesaconitine in all parts of the plant. In 1986 a case of sudden death of a woman traveler was autopsied in Okinawa by the author. The cause of her death was revealed to be aconite poisoning in 1987 by detecting the Aconitum alkaloids in her blood by the gas chromatography / selected ion monitoring (GC/SIM) method, newly developed for this case. The husband was suspected of the murder by the fact that he insured her life for 185 million yen. In 1991 he was arrested and indicted on a charge of murder of the wife. However, the time lag between the time of her death and of her separation from the husband was still unexplainable. Just before the indictment the police disclosed the fact that tetrodotoxin, the pufferfish toxin, was also detected in the victim's blood. Then, we executed the animal experiments to clarify the toxicity of aconitine in the presence of tetrodotoxin. Our experiments revealed a delaying effect of tetrodotoxin on the time of death by aconitine poisoning, probably because the two toxins are mutually antagonistic in the sodium channel in excitable membranes. The toxico-kinetics of aconitine was also investigated by measuring it in the biological specimens of intoxicated animals, The method of GC/SIM enabled us to obtain the results that the elimination velocity of aconitine in mice is proportional to the blood concentration. Further investigations have to be continued to clarify some complicated effect of the coadministration of the two toxins
Aconitine (AC), mesaconitine (MA), hypaconitine (HA) (50 μg/kg i.v.), bezoylaconine (BA), benzoylmesaconine (BM) and benzoylhypaconine (BH) (5 mg/kg i.v.) produced a weak temporary hypotension in rats which was blocked to some extent by atropine. In the isolated guinea pig right atria, MA and HA (3x10 -8 g/ml) mediated a positive inotropic action and a positive chronotropic action. At the higher conentration of 10 -7 g/ml, AC, MA and HA exhibited the above actions followed by inhibition of contractions and disorder of the beating rate. In the isolated guinea pig ileum, AC, MA and HA (>10 -6 g/ml) caused a contraction which was completely blocked by atropine. In the isolated guinea pig vas deferens, AC, MA and HA (>10 -5 g/ml) elicited a contraction which was completely obliterated by phentolamine. In the isolated guinea pig hypogastric nerve-vas deferens, the isolated rabbit mesenteric nerve-jejunum and the isolated rat phrenic nerve-diaphragm, responses induced by the electrical stimulation of the corresponding nerves were inhibited by AC, MA and HA (10 -6-10 -5 g/ml). Some of the mechanisms of the above actions induced by these alkaloids are discussed. These alkaloids more or less potentiated the hexobarbital anesthesia, inhibited the revolution of the wheel cage, and reduced the rectal temperature in mice, indicating that they have a depressant activity on the central nervous system.