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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/10/08 09:04:15」(JST)

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Aconitine is a toxin produced by the Aconitum plant, also known as devil’s helmet or monkshood. Monkshood is notorious for its toxic properties. In China, aconitine is also used in small doses as an analgesic .

Uses

Aconitine was previously used as an antipyretic and analgesic and still has some limited application in herbal medicine although the narrow therapeutic index makes calculating appropriate dosage difficult.^[1]

Structure and reactivity

Aconitine belongs to the family of aconitum alkaloids and is barely soluble in water,^[2] ^[3] but very soluble in organic solvents such as chloroform or diethyl ether. Aconitine is also soluble in mixtures of alcohol and water if the concentration of alcohol is high enough. Aconitine is very toxic due to several reactive groups. The nitrogen in one of the six-membered ring structure can easily form salts and ions. This turns the molecule into a structure with high binding affinity for polar and lipophilic structures (such as cell membranes and receptors) and makes it possible for the molecule to pass the blood-brain barrier.^[4] The acetoxyl group at the c8 position can readily be replaced by a methoxy group, by heating aconitine in methanol, to produce a 8-deacetyl-8-o-methyl derivatives.^[5] If aconitine is heated in its dry state, it undergoes a pyrolysis to form pyroaconitine((1α,3α,6α,14α,16β)-20-Ethyl-3,13-dihydroxy-1,6,16-trimethoxy-4-(methoxymethyl)-15-oxoaconitan-14-yl benzoate) with the chemical formula C₃₂H₄₃NO₉.^[6]^[7]

Synthesis

Aconitine is synthesized by the monkshood plant via the terpenoid biosynthesis pathway (MEP chloroplast pathway).

Mechanism of action

Aconitine can interact with the voltage-dependent sodium-ion channels, which are proteins in the cell membranes of excitable tissues, such as cardiac and skeletal muscles and neurons. These proteins that are highly selective for sodium-ions. They open very fast to depolarize the cell membrane potential, causing the upstroke of an action potential. Normally, the sodium channels close very rapidly, but the depolarization of the membrane potential causes the opening (activation) of potassium channels and potassium-efflux, which results in repolarization the membrane potential.

Aconitine binds to the receptor at the neurotoxin binding site 2 on the alpha-subunit of the channel protein.^[8] This binding results in a sodium-ion channel that stays open longer. Aconitine suppresses the conformational change in the sodium-ion channel from the active state to the inactive state. The membrane stays depolarized due to the constant sodium-influx (which is 10-1000 fold greater than the potassium efflux). As a result, the membrane cannot be repolarized. The binding of aconitine to the channel also leads to the channel to change conformation from the inactive state to the active state at a more negative voltage.^[9] In neurons, aconitine increases the permeability of the membrane for sodium-ions, resulting in a huge sodium-influx in the axon terminal. As a result, the membrane depolarizes rapidly. Due to the strong depolarization, the permeability of the membrane for potassium-ions increases fast, resulting in a potassium-reflux to release the positive charge out of the cell. Not only the permeability for potassium-ions but also the permeability for calcium-ions increases as a result of the depolarization of the membrane. A calcium-influx takes place. The increase of the calcium concentration in the cell stimulates the release of the neurotransmitter acetylcholine into the synaptic cleft. Acetylcholine binds to acetylcholine receptors at the postsynaptic membrane to open the sodium-channels there, generating a new action potential. Research with mouse nerve-hemidiaphragm muscle preparation indicate that at low concentrations (<0,1 microM) aconitine increases the electrically evoked acetylcholine release causing an induced muscle tension.^[10] Action potentials are generated more often at this concentration. At higher concentration (0.3–3 microM) aconitine decreases the electrically evoked acetylcholine release, resulting in a decrease in muscle tension. At high concentration (0.3–3 microM), the sodium-ion channels are constantly activated, transmission of action potentials is suppressed, leading to non-excitable target cells or paralysis.

Metabolism

Aconitine is metabolized by cytochrome P450 isozymes (CYPs). There has been a research in 2011 in China to investigate in-depth the CYPs involved in aconitine metabolism in human liver microsomes.^[11] It has been estimated that more than 90 percent of currently available human drug metabolism can be attributed to eight main enzymes (CYP 1A2, 2C9, 2C8, 2C19, 2D6, 2E1, 3A4, 3A5).^[12] The researchers used recombinants of these eight different CYPs and incubated it with aconitine. To initiate the metabolism pathway the presence of NADPH was needed. Six CYP-mediated metabolites (M1–M6) were found by liquid-chromatography, these six metabolites were characterized by mass-spectrometry. The six metabolites and the involved enzymes are summarized in the following table:

Metabolite	Name	Involved CYPs
M1	O-Demethyl-aconitine	CYP3A4, CYP3A5, CYP2D6, CYP2C8
M2	16-O-Demethyl-aconitine	CYP3A4, CYP3A5, CYP2D6, CYP2C9
M3	N-deethyl-aconitine	CYP3A4, CYP3A5, CYP2D6, CYP2C9
M4	O-didemethyl-aconitine	CYP3A5, CYP2D6
M5	3-Dehydrogen-aconitine	CYP3A4, CYP3A5
M6	Hydroxyl-aconitine	CYP3A5, CYP2D6

Selective inhibitors were used to determine the involved CYPs in the aconitine metabolism. The results indicate that aconitine was mainly metabolized by CYP3A4, 3A5 and 2D6. CYP2C8 and 2C9 had a minor role to the aconitine metabolism, whereas CYP1A2, 2E1 and 2C19 did not produce any aconitine metabolites at all. The proposed metabolic pathways of aconitine in human liver microsomes and the CYPs involved to it are summarized in the table above.

Toxicity

The toxic effects of Aconitine have been tested in a variety of different test animals, including mammals (dog, cat, guinea pig, mouse, rat and rabbit), frogs and pigeons. Depending on the route of exposure, the observed toxic effects were: local anesthetic effect, diarrhea, convulsions, arrhythmias or death.^[13] According to a review of different reports of aconite poisoning in humans the following clinical features were observed:^[1]

Neurological: paresthesia and numbness of face, perioral area and four limbs; muscle weakness in four limbs;
Cardiovascular: hypotension, palpitations, chest pain, bradycardia, sinus tachycardia, ventricular ectopics, ventricular arrhythmias, and junctional rhythm;
Ventricular arrhythmias;
Gastrointestinal: nausea, vomiting, abdominal pain, and diarrhea;
Others: dizziness, hyperventilation, sweating, difficulty breathing, confusion, headache, and lacrimation.

Progression of symptoms: the first symptoms of aconitine poisoning appear approximately 20 minutes to 2 hours after oral intake and include paraesthesia, sweating and nausea. This leads to severe vomiting, colicky diarrhea, intense pain and then paralysis of the skeletal muscles. Following the onset of life-threatening arrhythmia, including ventricular tachycardia and ventricular fibrillation, death finally occurs as a result of respiratory paralysis or cardiac arrest.^[14]

LD50 values for mice are 1 mg/kg orally, 0.100 mg/kg intravenously, 0.270 mg/kg intraperitoneally and 0.270 mg/kg subcutaneously. The lowest published lethal dose (LDLo) for mice is 1 mg/kg orally and 0.100 mg/kg intraperitoneally. The lowest published toxic dose (TDLo) for mice is 0.0549 mg/kg subcutaneously. LD50 value for rats is 0.064 mg/kg intraveneously. The LDLo for rats is 0.040 mg/kg intravenously and 0.250 mg/kg intraperitoneally. The TDLo for rats is 0.040 mg/kg parenterally. For an overview of more test animal results (LD50, LDLo and TDLo) see the following table.^[13]

Species Observed	Type of Test	Route of Exposure	Dose Data (mg/kg)	Toxic Effects
Human	LDLo	Oral	0.028	Behavioral: excitement Gastrointestinal: hypermotility, diarrhea Gastrointestinal: other changes
Human	LDLo	Oral	0.029	Details of toxic effects not reported other than lethal dose value
Cat	LD₅₀	Intravenous	0.080	Behavioral: convulsions or effect on seizure threshold
Cat	LDLo	Subcutaneous	0.100	Details of toxic effects not reported other than lethal dose value
Guinea pig	LD₅₀	Intravenous	0.060	Behavioral: convulsions or effect on seizure threshold
Guinea pig	LDLo	Subcutaneous	0.050	Details of toxic effects not reported other than lethal dose value
Guinea pig	LDLo	Intravenous	0.025	Cardiac: arrhythmias (including changes in conduction)
Mouse	LD₅₀	Intraperitoneal	0.270	Details of toxic effects not reported other than lethal dose value
Mouse	LD₅₀	Intravenous	0.100	Sense Organs and Special Senses (Eye): lacrimation Behavioral: convulsions or effect on seizure threshold Lungs, Thorax, or Respiration: dyspnea
Mouse	LD₅₀	Oral	1	Details of toxic effects not reported other than lethal dose value
Mouse	LD₅₀	Subcutaneous	0.270	Details of toxic effects not reported other than lethal dose value
Mouse	LDLo	Intraperitoneal	0.100	Details of toxic effects not reported other than lethal dose value
Mouse	LDLo	Oral	1	Behavioral: convulsions or effect on seizure threshold Cardiac: arrhythmias (including changes in conduction) Gastrointestinal: hypermotility, diarrhea
Mouse	TDLo	Subcutaneous	0.0549	Peripheral Nerve and Sensation: local anesthetic Behavioral: analgesia
Rabbit	LDLo	Subcutaneous	0.131	Details of toxic effects not reported other than lethal dose value
Rat	LD₅₀	Intravenous	0.080	Behavioral: convulsions or effect on seizure threshold
Rat	LD₅₀	Intravenous	0.064	Details of toxic effects not reported other than lethal dose value
Rat	LDLo	Intraperitoneal	0.250	Cardiac: other changes Lungs, Thorax, or Respiration: dyspnea
Rat	LDLo	Intravenous	0.040	Cardiac: arrhythmias (including changes in conduction)
Rat	TDLo	Parenteral	0.040	Cardiac: arrhythmias (including changes in conduction)
Frog	LDLo	Subcutaneous	0.586	Details of toxic effects not reported other than lethal dose value
Pigeon	LDLo	Subcutaneous	0.066	Details of toxic effects not reported other than lethal dose value

note that LD₅₀ means lethal dose, 50 percent kill; LDLo means lowest published lethal dose; TDLo means lowest published toxic dose

For humans the lowest published oral lethal dose of 28 μg/kg was reported in 1969.

Diagnosis and treatment

For the analysis of the Aconitum alkaloids in biological specimens such as blood, serum and urine, several GC-MS methods have been described. These employ a variety of extraction procedures followed by derivatisation to their trimethylsilyl derivatives. New sensitive HPLC-MS methods have been developed as well, usually preceded by SPE purification of the sample.^[14] The antiarrhythmic drug lidocaine has been reported to be an effective treatment of aconitine poisoning of a patient. Considering the fact that aconitine acts as an agonist of the sodium channel receptor, antiarrhythmic agents which block the sodium-channel (Vaughan-Williams' classification I) might be the first choice for the therapy of aconitine induced arrhythmias.^[15] Animal experiments have shown that the mortality of aconitine is lowered by tetrodotoxin. The toxic effects of aconitine were attenuated by tetrodotoxin, probably due to their mutual antagonistic effect on excitable membranes.^[16] Also Paeoniflorin seems to have a detoxifying effect on the acute toxicity of aconitine in test animals. This may result from alternations of pharmacokinetic behavior of aconitine in the animals due to the pharmacokinetic interaction between aconitine and paeoniflorin.^[17] In addition in emergencies to assist someone after calling 911 one can wash the stomach using either tannic acid or powdered charcoal. Heart stimulants such as strong coffee or caffeine may also help.^[18]

Famous poisonings

During the Indian Rebellion of 1857, a British detachment were the subject of attempted poisoning with aconitine by the Indian regimental chefs. The plot was thwarted by John Nicholson who, having detected the plot, interrupted the British officers just as they were about to consume the poisoned meal. The chefs refused to taste their own preparation, whereupon it was force fed to a monkey who "expired on the spot". The chefs were hanged.

Aconitine was the poison used by George Henry Lamson in 1881 to murder his brother-in-law in order to secure an inheritance. Lamson had learned about aconitine as a medical student from professor Robert Christison, who had taught that it was undetectable—but forensic science had improved since Lamson's student days.^[19]^[20]^[21]

Aconitine was also made famous by its use in Oscar Wilde's 1891 story "Lord Arthur Savile's Crime". Aconite also plays a prominent role in James Joyce's Ulysses, in which the protagonist Leopold Bloom's father used pastilles of the chemical to commit suicide.

In 1953 aconitine was used by a Soviet biochemist and poison developer Grigory Mairanovsky in experiments with prisoners in the secret NKVD laboratory in Moscow. He admitted killing around 10 people using the poison.^[22]

In 2004 Canadian actor Andre Noble died from aconitine poisoning. He accidentally ate some monkshood while he was on a hike with his aunt in Newfoundland.

In 2009 Lakhvir Singh of Feltham, west London, used aconitine to poison the food of her ex-lover (who died as a result of the poisoning) and his current fiancée. Singh received a life sentence for the murder.^[23]

References

^ ^a ^b Chan TY (2009). "Aconite poisoning". Clinical Toxicology 47 (4): 279–285. doi:10.1080/15563650902904407. PMID 19514874.
^ [http://www.sigmaaldrich.com/catalog/product/si gma/a8001?lang=en "Aconitine"] Check |url= scheme (help). Sigma Aldrich.
^ "Aconitine sc-202441 Material Safety Data Sheet" (pdf). Santa Cruz Biotechnology.
^ Dewick PM (2002). Medicinal Natural Products. A Biosynthetic Approach (2nd ed.). Wiley. ISBN 0-471-49640-5.
^ Desai HK, Joshi BS, Ross SA, Pelletier SW (1989). "Methanolysis of the C-8 Acetoxyl Group in Aconitine-Type Alkaloids: A Partial Synthesis of Hokbusine A". Journal of Natural Products 52 (4): 720–725. doi:10.1021/np50064a009.
^ Pelletier SW, Mody NV (1979). "Chapter 1 The Structure and Synthesis of C₁₉-Diterpenoid Alkaloids". In Manske RH, Rodrigo R. The Alkaloids: Chemistry and Physiology 17. p. 4. doi:10.1016/S1876-0813(08)60296-1.
^ "Pyroaconitine ChemSpider ID: 10211301". Chemspider.
^ Gutser UT, Friese J, Heubach JF, Matthiesen T, Selve N, Wilffert B, Gleitz J (1998). "Mode of antinociceptive and toxic action of alkaloids of Aconitum species". Naunyn Schmiedeberg's Archive of Pharmacology 357 (1): 39–48. PMID 9459571.
^ Benoit E (1998). "Comptes Rendus des Séances de la Société de Biologie et de ses Filiales" [Mechanism of action of neurotoxins acting on the inactivation of voltage-gated sodium channels] (in French) 192 (3). pp. 409–436. PMID 9759381.
^ Okazaki M, Kimura I, Kimura M (1994). "Aconitine-induced increase and decrease of acetylcholine release in the mouse phrenic nerve-hemidiaphragm muscle preparation" (pdf). Japanese Journal of Pharmacology 66 (4): 421–426. doi:10.1254/jjp.66.421. PMID 7723217.
^ Tang L, Ye L, Ly C, Zheng Z, Gong Y, Liu Z (2011). "Involvement of CYP3A4/5 and CYP2D6 in the metabolism of aconitine using human liver microsomes and recombinant CYP450 enzymes". Toxicology Letters 202 (1): 47–54. doi:10.1016/j.toxlet.2011.01.019. PMID 21277363.
^ Bertilsson L, Lou YQ, Du YL, Liu Y, Kuang TY, Liao XM, Wang KY, Reviriego J, Iselius L, Sjöqvist F (1992). "Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin". Clinical Pharmacology and Therapeutic 51 (4): 388–397. PMID 1345344.
^ ^a ^b "RTECS". Oct 2011.
^ ^a ^b Beike J, Frommherz L, Wood M, Brinkmann B, Köhler H (2004). "Determination of aconitine in body fluids by LC-MS-MS". International Journal of Legal Medicine 118 (5): 289–293. doi:10.1007/s00414-004-0463-2. PMID 15674996.
^ Tsukada K, Akizuki S, Matsuoka Y, Irimajiri S (1992). "A case of aconitine poisoning accompanied by bidirectional ventricular tachycardia treated with lidocaine". Kokyu To Junkan (in Japanese) 40 (10): 1003–1006. PMID 1439251.
^ Ohno Y, Chiba S, Uchigasaki S, Uchima E, Nagamori H, Mizugaki M, Ohyama Y, Kimura K, Suzuki Y (1992). "The influence of tetrodotoxin on the toxic effects of aconitine in vivo" (pdf). Tohoku Journal of Experimental Medicine 167 (2): 155–158. doi:10.1620/tjem.167.155. PMID 1475787.
^ Fan YF, Xie Y, Liu L, Ho HM, Wong YF, Liu ZQ, Zhou H (2011). "Paeoniflorin reduced acute toxicity of aconitine in rats is associated with the pharmacokinetic alteration of aconitine". Journal of Ethnopharmacology 141 (2): 701–708. doi:10.1016/j.jep.2011.09.005. PMID 21930193.
^ Sax N. Irving. Dangerous Properties of Industrial Materials Fifth Edition New York: Van Nostrand Reinhold Company Inc. , ISBN 0-442-27373-8 Library of Congress Catalog Card Number 78-20812
^ Macinnis, Peter (2006). It's True! You Eat Poison Every Day. Allen & Unwin. pp. 80–81. ISBN 9781741146264.
^ Macinnis, P. (2005). Poisons: From Hemlock to Botox and the Killer Bean of Calabar. Arcade Publishing. pp. 25–26. ISBN 1-55970-761-5.
^ Parry, L. A.; Wright, W. H. (2000). Some Famous Medical Trials. Beard Books. p. 103. ISBN 1-58798-031-2.
^ Лаборатория Икс [Laboratory X]. Novaya Gazeta (in Russian). 2010-05-06. Retrieved 2013-04-08.
^ "Poisoning in west London in 2009". BBC TV News. 2010-02-10.

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1. 小児における有毒植物の誤飲：臨床症状および評価potentially toxic plant ingestions in children clinical manifestations and evaluation [show details]
…vomiting, dizziness, blurred vision or diplopia, and altered mental status . Fatalities are rare. Aconitine and related alkaloids are found in Aconitum napellus (monkshood) and other Aconitum species. These …
2. 小児における有毒植物の誤飲およびニコチン中毒：マネージメントtoxic plant ingestions and nicotine poisoning in children management [show details]
…measures . Ventricular tachycardia or fibrillation and torsades de pointes are features of monkshood (aconitine), false hellebore, and yew toxicity Ventricular arrhythmias may be initially treated with amiodarone…
3. ハーブ剤および栄養補助食品による肝毒性hepatotoxicity due to herbal medications and dietary supplements [show details]
…product or to modify its toxicity . Toxicity is generally observed with preparations that contain aconitine, podophyllin, or anticholinergics . Jin Bu Huan (Lycopodium serratum) has been used for over 1000…

English Journal

Simultaneous detection of 22 toxic plant alkaloids (aconitum alkaloids, solanaceous tropane alkaloids, sophora alkaloids, strychnos alkaloids and colchicine) in human urine and herbal samples using liquid chromatography-tandem mass spectrometry.

Ng SW, Ching CK, Chan AY, Mak TW.Author information Hospital Authority Toxicology Reference Laboratory, Princess Margaret Hospital, Hong Kong.AbstractA liquid chromatography-tandem mass spectrometry method for simultaneous detection of 22 toxic plant alkaloids, including aconitum alkaloids and their hydrolyzed products (aconitine, hypaconitine, mesaconitine, yunaconitine, crassicauline A, benzoylaconine, benzoylmesaconine, benzoylhypaconine, deacetylyunaconitine, deacetylcrassicauline A), solanaceous tropane alkaloids (atropine, anisodamine, scopolamine, anisodine), sophora alkaloids (matrine, sophoridine, oxymatrine, cytisine, N-methylcytisine), strychnos alkaloids (brucine, strychnine) and colchicine, in herbal and urine samples was developed and validated. Following sample preparation by liquid-liquid extraction, chromatographic separation was achieved on Eclipse XDB C8 column. Identification was based on two multiple reaction monitoring transitions and the relative ion intensity. Method selectivity was demonstrated. The limits of detection were 5ng/mL for all analytes, except 50ng/mL for cytisine. The herbal matrix effects ranged from 89% to 118%, whereas the urine matrix effects were between 91% and 109% for all analytes except cytisine (57%) and N-methylcytisine (67%). The urine extraction recovery ranged from 74% to 110% for all analytes, except cytisine (15%) and oxymatrine (30%). With the good extraction efficiency of the other major sophora alkaloids, the relatively low extraction recovery of the minor sophora alkaloids cytisine and oxymatrine did not affect identification of sophora alkaloids as a group. Carry-over was minimal at less than 0.1%. The method was successfully applied in analysis of 170 cases of suspected herbal poisoning, with aconitum alkaloids, sophora alkaloids, solanaceous tropane alkaloids, and strychnos alkaloids being detected in 53, 42, 18, and 6 cases, respectively.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.J Chromatogr B Analyt Technol Biomed Life Sci.2013 Dec 30;942-943:63-9. doi: 10.1016/j.jchromb.2013.10.020. Epub 2013 Oct 22.
A liquid chromatography-tandem mass spectrometry method for simultaneous detection of 22 toxic plant alkaloids, including aconitum alkaloids and their hydrolyzed products (aconitine, hypaconitine, mesaconitine, yunaconitine, crassicauline A, benzoylaconine, benzoylmesaconine, benzoylhypaconine, deac
PMID 24216273

P-glycoprotein is responsible for the poor intestinal absorption and low toxicity of oral aconitine: In vitro, in situ, in vivo and in silico studies.

Yang C, Zhang T, Li Z, Xu L, Liu F, Ruan J, Liu K, Zhang Z.Author information Key Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Pharmacology and Toxicology, Beijing, China. Electronic address: yangsophia76@hotmail.com.AbstractAconitine (AC) is a highly toxic alkaloid from bioactive plants of the genus Aconitum, some of which have been widely used as medicinal herbs for thousands of years. In this study, we systematically evaluated the potential role of P-glycoprotein (P-gp) in the mechanisms underlying the low and variable bioavailability of oral AC. First, the bidirectional transport of AC across Caco-2 and MDCKII-MDR1 cells was investigated. The efflux of AC across monolayers of these two cell lines was greater than its influx. Additionally, the P-gp inhibitors, verapamil and cyclosporin A, significantly decreased the efflux of AC. An in situ intestinal perfusion study in rats showed that verapamil co-perfusion caused a significant increase in the intestinal permeability of AC, from 0.22×10(-5) to 2.85×10(-5)cm/s. Then, the pharmacokinetic profile of orally administered AC with or without pre-treatment with verapamil was determined in rats. With pre-treatment of verapamil, the maximum plasma concentration (Cmax) of AC increased sharply, from 39.43 to 1490.7ng/ml. Accordingly, a 6.7-fold increase in the area under the plasma concentration-time curve (AUC0-12h) of AC was observed when co-administered with verapamil. In silico docking analyses suggested that AC and verapamil possess similar P-gp recognition mechanisms. This work demonstrated that P-gp is involved in limiting the intestinal absorption of AC and attenuating its toxicity to humans. Our data indicate that potential P-gp-mediated drug-drug interactions should be considered carefully in the clinical application of aconite and formulations containing AC.
Toxicology and applied pharmacology.Toxicol Appl Pharmacol.2013 Dec 15;273(3):561-8. doi: 10.1016/j.taap.2013.09.030. Epub 2013 Oct 9.
Aconitine (AC) is a highly toxic alkaloid from bioactive plants of the genus Aconitum, some of which have been widely used as medicinal herbs for thousands of years. In this study, we systematically evaluated the potential role of P-glycoprotein (P-gp) in the mechanisms underlying the low and variab
PMID 24120885

Susceptibility to life-threatening ventricular arrhythmias in an animal model of paradoxical sleep deprivation.

Joukar S, Ghorbani-Shahrbabaki S, Hajali V, Sheibani V, Naghsh N.Author information Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, Iran; Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran; Department of Physiology and Pharmacology, School of Medicine Kerman University of Medical Sciences, Kerman, Iran. Electronic address: sjokar@gmail.com.AbstractBACKGROUND: According to some reports regarding the increase of cardiac events following sleep deprivation, our study was conducted to clarify the effects of rapid eye movement (REM) sleep deprivation on susceptibility to lethal ventricular arrhythmias in rat.
Sleep medicine.Sleep Med.2013 Dec;14(12):1277-82. doi: 10.1016/j.sleep.2013.07.008. Epub 2013 Sep 8.
BACKGROUND: According to some reports regarding the increase of cardiac events following sleep deprivation, our study was conducted to clarify the effects of rapid eye movement (REM) sleep deprivation on susceptibility to lethal ventricular arrhythmias in rat.METHODS: The animal groups included the
PMID 24091142

Japanese Journal

NATURAL RESOURCE LETTER : Diversity in aconitine alkaloid profile of Aconitum plants in Hokkaido contrasts with their genetic similarity

Journal of natural medicines 69(1), 154-164, 2015
NAID 40020305812

Successful Rescue of a Patient with Acute Aconitine Poisoning Complicated by Polycystic Renal Hemorrhage

Journal of Nippon Medical School 82(5), 257-261, 2015
NAID 130005108930

Termination of Aconitine-Induced Atrial Fibrillation by the KACh-Channel Blocker Tertiapin: Underlying Electrophysiological Mechanism

Journal of Pharmacological Sciences 125(4), 406-414, 2014
NAID 130004677795

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「アコニチン」

Aconitine
Names
	IUPAC name (1α,3α,6α,14α,16β)-8-(acetyloxy)-20-ethyl-3,13,15-trihydroxy-1,6,16-trimethoxy-4-(methoxymethyl)aconitan-14-yl benzoate
	Other names Acetylbenzoylaconine
Identifiers
CAS Registry Number	302-27-2
ChEBI	CHEBI:2430
ChEMBL	ChEMBL507036
ChemSpider	214292
	InChI InChI=1S/C34H47NO11/c1-7-35-15-31(16-41-3)20(37)13-21(42-4)33-19-14-32(40)28(45-30(39)18-11-9-8-10-12-18)22(19)34(46-17(2)36,27(38)29(32)44-6)23(26(33)35)24(43-5)25(31)33/h8-12,19-29,37-38,40H,7,13-16H2,1-6H3/t19-,20-,21+,22-,23+,24+,25-,26?,27+,28-,29+,31+,32-,33+,34-/m1/s1 ; Key: XFSBVAOIAHNAPC-XTHSEXKGSA-N ; InChI=1/C34H47NO11/c1-7-35-15-31(16-41-3)20(37)13-21(42-4)33-19-14-32(40)28(45-30(39)18-11-9-8-10-12-18)22(19)34(46-17(2)36,27(38)29(32)44-6)23(26(33)35)24(43-5)25(31)33/h8-12,19-29,37-38,40H,7,13-16H2,1-6H3/t19-,20-,21+,22-,23+,24+,25-,26?,27+,28-,29+,31+,32-,33+,34-/m1/s1; Key: XFSBVAOIAHNAPC-XTHSEXKGBF ;
IUPHAR/BPS	2617
Jmol-3D images	Image; Image
PubChem	245005
	SMILES COC[C@]12CN(C)[C@@H]3[C@H]4[C@H](OC)C1[C@@]3([C@H](C[C@H]2O)OC)[C@@H]5C[C@]6(O)[C@@H](OC)[C@H](O)[C@@]4(OC(C)=O)[C@H]5C6OC(=O)c7ccccc7 ; O=C(O[C@H]5[C@]3(O)C[C@H]4[C@@]16C2N(CC)C[C@]([C@H]1[C@@H](OC)[C@@H]2[C@@](OC(=O)C)([C@@H](O)[C@@H]3OC)[C@H]45)(COC)[C@H](O)C[C@@H]6OC)c7ccccc7 ;
UNII	X8YN71D5WC
Properties
Chemical formula	C34H47NO11
Molar mass	645.73708
Appearance	solid
Melting point	203 to 204 °C (397 to 399 °F; 476 to 477 K)
Solubility in water	H2O: 0.3 mg/mL ethanol: 35 mg/mL
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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	Infobox references

　　[★]

英: aconitine
関: 附子

トリカブトに含まれるアルカロイド

参考

1.

http://ja.wikipedia.org/wiki/%E3%82%A2%E3%82%B3%E3%83%8B%E3%83%81%E3%83%B3

[pmid19514874-1] Chan TY (2009). "Aconite poisoning". Clinical Toxicology 47 (4): 279–285. doi:10.1080/15563650902904407. PMID 19514874.

[2] [http://www.sigmaaldrich.com/catalog/product/si gma/a8001?lang=en "Aconitine"] Check |url= scheme (help). Sigma Aldrich.

[3] "Aconitine sc-202441 Material Safety Data Sheet" (pdf). Santa Cruz Biotechnology.

[4] Dewick PM (2002). Medicinal Natural Products. A Biosynthetic Approach (2nd ed.). Wiley. ISBN 0-471-49640-5.

[5] Desai HK, Joshi BS, Ross SA, Pelletier SW (1989). "Methanolysis of the C-8 Acetoxyl Group in Aconitine-Type Alkaloids: A Partial Synthesis of Hokbusine A". Journal of Natural Products 52 (4): 720–725. doi:10.1021/np50064a009.

[6] Pelletier SW, Mody NV (1979). "Chapter 1 The Structure and Synthesis of C₁₉-Diterpenoid Alkaloids". In Manske RH, Rodrigo R. The Alkaloids: Chemistry and Physiology 17. p. 4. doi:10.1016/S1876-0813(08)60296-1.

[7] "Pyroaconitine ChemSpider ID: 10211301". Chemspider.

[8] Gutser UT, Friese J, Heubach JF, Matthiesen T, Selve N, Wilffert B, Gleitz J (1998). "Mode of antinociceptive and toxic action of alkaloids of Aconitum species". Naunyn Schmiedeberg's Archive of Pharmacology 357 (1): 39–48. PMID 9459571.

[9] Benoit E (1998). "Comptes Rendus des Séances de la Société de Biologie et de ses Filiales" [Mechanism of action of neurotoxins acting on the inactivation of voltage-gated sodium channels] (in French) 192 (3). pp. 409–436. PMID 9759381.

[10] Okazaki M, Kimura I, Kimura M (1994). "Aconitine-induced increase and decrease of acetylcholine release in the mouse phrenic nerve-hemidiaphragm muscle preparation" (pdf). Japanese Journal of Pharmacology 66 (4): 421–426. doi:10.1254/jjp.66.421. PMID 7723217.

[11] Tang L, Ye L, Ly C, Zheng Z, Gong Y, Liu Z (2011). "Involvement of CYP3A4/5 and CYP2D6 in the metabolism of aconitine using human liver microsomes and recombinant CYP450 enzymes". Toxicology Letters 202 (1): 47–54. doi:10.1016/j.toxlet.2011.01.019. PMID 21277363.

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[rtecs-13] "RTECS". Oct 2011.

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[15] Tsukada K, Akizuki S, Matsuoka Y, Irimajiri S (1992). "A case of aconitine poisoning accompanied by bidirectional ventricular tachycardia treated with lidocaine". Kokyu To Junkan (in Japanese) 40 (10): 1003–1006. PMID 1439251.

[16] Ohno Y, Chiba S, Uchigasaki S, Uchima E, Nagamori H, Mizugaki M, Ohyama Y, Kimura K, Suzuki Y (1992). "The influence of tetrodotoxin on the toxic effects of aconitine in vivo" (pdf). Tohoku Journal of Experimental Medicine 167 (2): 155–158. doi:10.1620/tjem.167.155. PMID 1475787.

[17] Fan YF, Xie Y, Liu L, Ho HM, Wong YF, Liu ZQ, Zhou H (2011). "Paeoniflorin reduced acute toxicity of aconitine in rats is associated with the pharmacokinetic alteration of aconitine". Journal of Ethnopharmacology 141 (2): 701–708. doi:10.1016/j.jep.2011.09.005. PMID 21930193.

[18] Sax N. Irving. Dangerous Properties of Industrial Materials Fifth Edition New York: Van Nostrand Reinhold Company Inc. , ISBN 0-442-27373-8 Library of Congress Catalog Card Number 78-20812

[19] Macinnis, Peter (2006). It's True! You Eat Poison Every Day. Allen & Unwin. pp. 80–81. ISBN 9781741146264.

[20] Macinnis, P. (2005). Poisons: From Hemlock to Botox and the Killer Bean of Calabar. Arcade Publishing. pp. 25–26. ISBN 1-55970-761-5.

[21] Parry, L. A.; Wright, W. H. (2000). Some Famous Medical Trials. Beard Books. p. 103. ISBN 1-58798-031-2.

[22] Лаборатория Икс [Laboratory X]. Novaya Gazeta (in Russian). 2010-05-06. Retrieved 2013-04-08.

[23] "Poisoning in west London in 2009". BBC TV News. 2010-02-10.

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aconitine