乌头碱
| 此條目需要擴充。 (2009年12月22日) |
烏頭鹼（Aconitine）是一種生物鹼毒素。是常用中藥烏頭屬中所含有的一種化學物質，具強烈毒性,口服0.2mg左右即能使人中毒，3-5mg即可致死。[1]民间常用草乌、川乌等植物来泡制药酒，但这种药酒可能是极端危险的，也经常因此出现中毒甚至死亡的情况。[2][3]
| 烏頭鹼 | |
|---|---|
| IUPAC名 8-(acetyloxy)-20-ethyl-3α,13,15-trihydroxy-1α,6α,16β-trimethoxy-4-(methoxymethyl)aconitan-14α-yl benzoate | |
| 别名 | Acetylbenzoylaconine 乙酰苯甲酰阿康碱 |
| 识别 | |
| CAS号 | 302-27-2 |
| PubChem | 245005 |
| ChemSpider | 214292 |
| SMILES |
|
| ChEBI | 2430 |
| KEGG | C06091 |
| IUPHAR配体 | 2617 |
| 性质 | |
| 化学式 | C34H47NO11 |
| 摩尔质量 | 645.74 g·mol−1 |
| 外观 | 固體 |
| 熔点 | 203 °C（476 K） |
| 溶解性（水） | H2O: 0.3 mg/mL 乙醇: 35 mg/mL |
| 危险性 | |
| GHS危险性符号 | |
| GHS提示词 | Danger |
| H-术语 | H300, H330 |
| P-术语 | P260, P264, P270, P271, P284, P301+310, P304+340, P310, P320, P321, P330, P403+233, P405, P501 |
| 性质 | |
| 化学式 | C34H47NO11 |
| 摩尔质量 | 645.73708 g·mol⁻¹ |
| 危险性 | |
| NFPA 704 | 0 4 0 |
| 若非注明，所有数据均出自标准状态（25 ℃，100 kPa）下。 | |
用途 编辑
結構和反應性 编辑
附子屬和翠雀屬植物的生物活性分離物被歸類為去甲二萜生物碱。[5]根據C18碳的存在與否進一步細分。[6]烏頭鹼是一種C19去甲二萜生物碱，因為它含有C18。烏頭鹼幾乎不溶於水，但極易溶於有機溶劑，例如氯仿或乙醚。[7][8]如果酒精濃度足夠高，烏頭鹼也可溶於乙醇和水的混合物中。
像許多其他生物鹼一樣，烏頭鹼六元環的鹼性氮很容易形成鹽和離子，使其對極性和親脂性結構過血腦屏障。[9]
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.[10] 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.[11][12]
作用 编辑
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 are highly selective for sodium ions. They open very quickly 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 of the membrane potential.
Aconitine binds to the channel at the neurotoxin binding site 2 on the alpha subunit.[13] 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.[14] 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 rapidly, 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 μM) aconitine increases the electrically evoked acetylcholine release causing an induced muscle tension.[15] Action potentials are generated more often at this concentration. At higher concentration (0.3–3 μM) aconitine decreases the electrically evoked acetylcholine release, resulting in a decrease in muscle tension. At high concentration (0.3–3 μM), the sodium-ion channels are constantly activated, transmission of action potentials is suppressed, leading to non-excitable target cells or paralysis.
合成 编辑
Aconitine is biosynthesized by the monkshood plant via the terpenoid biosynthesis pathway (MEP chloroplast pathway).[16] Approximately 700 naturally occurring C19-diterpenoid alkaloids have been isolated and identified, but the biosynthesis of only a few of these alkaloids are well understood.[17]
Likewise, only a few alkaloids of the aconitine family have been synthesized in the laboratory. In particular, despite over one hundred years having elapsed since its isolation, the prototypical member of its family of norditerpenoid alkaloids, aconitine itself, represents a rare example of a well-known natural product that has yet to succumb to efforts towards its total synthesis. The challenge that aconitine poses to synthetic organic chemists is due to both the intricate interlocking hexacyclic ring system that make up its core and the elaborate collection of oxygenated functional groups at its periphery. A handful of simpler members of the aconitine alkaloids, however, have been prepared synthetically. In 1971, the Weisner group discovered the total synthesis of talatisamine (a C19-norditerpenoid).[18] In the subsequent years, they also discovered the total syntheses of other C19-norditerpenoids, such as chasmanine,[19] and 13-deoxydelphonine.[20]
The total synthesis of napelline (Scheme a) begins with aldehyde 100.[18] In a 7 step process, the A-ring of napelline is formed (104). It takes another 10 steps to form the lactone ring in the pentacyclic structure of napelline (106). An additional 9 steps creates the enone-aldehyde 107. Heating in methanol with potassium hydroxide causes an aldol condensation to close the sixth and final ring in napelline (14). Oxidation then gives rise to diketone 108 which was converted to (±)-napelline (14) in 10 steps.
A similar process is demonstrated in Wiesner's synthesis of 13-desoxydelphinone (Scheme c).[19] The first step of this synthesis is the generation of a conjugated dienone 112 from 111 in 4 steps. This is followed by the addition of a benzyl vinyl ether to produce 113. In 11 steps, this compound is converted to ketal 114. The addition of heat, DMSO and o-xylene rearranges this ketol (115), and after 5 more steps (±)-13-desoxydelphinone (15) is formed.
Lastly, talatisamine (Scheme d) is synthesized from diene 116 and nitrile 117.[20] The first step is to form tricycle 118 in 16 steps. After another 6 steps, this compound is converted to enone 120. Subsequently, this allene is added to produce photoadduct 121. This adduct group is cleaved and rearrangement gives rise to the compound 122. In 7 steps, this compound forms 123, which is then rearranged, in a similar manner to compound 114, to form the aconitine-like skeleton in 124. A racemic relay synthesis is completed to produce talatisamine (13).
More recently, the laboratory of the late David Y. Gin completed the total syntheses of the aconitine alkaloids nominine[21] and neofinaconitine.[22]
代謝 编辑
Aconitine is metabolized by cytochrome P450 isozymes (CYPs). There has been research in 2011 in China to investigate in-depth the CYPs involved in aconitine metabolism in human liver microsomes.[23] 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).[24] 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.
診斷和治療 编辑
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.[25] 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.[26] 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.[27] 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.[28] In addition, in emergencies, one can wash the stomach using either tannic acid or powdered charcoal. Heart stimulants such as strong coffee or caffeine may also help until professional help is available.[29]
著名中毒事件 编辑
During the Indian Rebellion of 1857, a British detachment was the target of attempted poisoning with aconitine by the Indian regimental cooks. 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 cooks 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.[30][31][32]
Rufus T. Bush, American industrialist and yachtsman, died on September 15, 1890, after accidentally taking a fatal dose of aconite.
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.[33]
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 Lakhvinder Cheema (who died as a result of the poisoning) and his current fiancée Aunkar Singh. Singh received a life sentence with a 23-year minimum for the murder on February 10, 2010.[34]
流行文化 编辑
烏頭鹼是古代世界最受歡迎的毒藥。普布利烏斯·奧維修斯·納索提到了眾所周知的繼母不喜歡繼子的問題，他寫道：
Lurida terribiles miscent aconita novercae.[35]
Fearsome stepmothers mix lurid aconites.
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 father to protagonist Leopold Bloom used pastilles of the chemical to commit suicide. Aconitine poisoning plays a key role in the murder mystery Breakdown by Jonathan Kellerman (2016). In Twin Peaks (season 3) Part 13, aconitine is suggested to poison the main character.[36]
Monk's Hood is the name of the third Cadfael Novel written in 1980 by Ellis Peters. The novel was made into an episode of the well known television series Cadfael starring Derek Jacobi.
毒性 编辑
烏頭鹼的毒性作用已在多種動物身上進行了測試有效，包括哺乳動物（狗、貓、豚鼠、小鼠、大鼠和兔子）、鴿、青蛙。觀察到的毒性作用有：局部麻醉、腹瀉、抽搐、心律失常、死亡。[37][38]
根據對人類附子中毒的不同報導的回顧，觀察到以下臨床特徵：[4]
- 神經系統：感覺異常和臉、口周區域和四肢麻木、肌肉無力。
- 心血管：低血壓、心悸、胸痛、心動過緩、竇性心動過速、室性異位及其他心律失常、室性心律失常、交界性心律
- 胃腸道：噁心、嘔吐、腹痛、腹瀉
- 其他：頭暈、過度換氣、出汗、呼吸困難、意識模糊、頭痛、流淚
烏頭鹼中毒的最初症狀出現在口服後約20分鐘至2小時，包括感覺異常、出汗、噁心。這會導致嚴重的嘔吐、絞痛性腹瀉、劇烈疼痛，然後骨骼肌麻痺。威脅生命的心律失常，包括室性心動過速、心室顫動，會因呼吸麻痺或心臟驟停而死亡。[25]
小鼠的LD50值為口服 1 mg/kg、靜脈 0.100 mg/kg、腹膜 0.270 mg/kg 和皮下 0.270 mg/kg。小鼠的最低致死量（LDLo）為口服 1 mg/kg 和腹腔 0.100 mg/kg。小鼠的最低中毒量（TDLo）為 0.0549 mg/kg 皮下注射。大鼠靜脈注射的LD50值為 0.064 mg/kg。大鼠的LDLo為靜脈注射 0.040 mg/kg和腹腔 0.250 mg/kg。大鼠的腸胃TDLo為 0.040 mg/kg。有關更多參見下表：LD50表示平均致死量；LDLo是指最低致死量；TDLo表示最低中毒量。[38]
| 物種 | 測試 | 路線 | 劑量（mg/kg） | 毒性 |
|---|---|---|---|---|
| 人類 | LDLo | 口服 | 0.028 | 行為：興奮 胃腸道：運動亢進、腹瀉、其他變化 |
| 人類 | LDLo | 口服 | 0.029 | 除致死劑量值外未報告詳情毒性作用 |
| 貓 | LD50 | 靜脈 | 0.080 | 行為：抽搐或對癲癇發作閾值的影響 |
| 貓 | LDLo | 皮下 | 0.100 | 除致死劑量值外未報告詳情毒性作用 |
| 豚鼠 | LD50 | 靜脈 | 0.060 | 行為：抽搐或對癲癇發作閾值的影響 |
| 豚鼠 | LDLo | 皮下 | 0.050 | 除致死劑量值外未報告詳情毒性作用 |
| 豚鼠 | LDLo | 靜脈 | 0.025 | 心臟：心律失常（包括傳導改變） |
| 小鼠 | LD50 | 腹腔 | 0.270 | 除致死劑量值外未報告詳情毒性作用 |
| 小鼠 | LD50 | 靜脈 | 0.100 | 感覺器官和特殊感覺（眼睛）：流淚 行為：抽搐或對癲癇發作閾值的影響 |
| 小鼠 | LD50 | 口服 | 1 | 除致死劑量值外未報告詳情毒性作用 |
| 小鼠 | LD50 | 皮下 | 0.270 | 除致死劑量值外未報告詳情毒性作用 |
| 小鼠 | LDLo | 腹腔 | 0.100 | 除致死劑量值外未報告詳情毒性作用 |
| 小鼠 | LDLo | 口服 | 1 | 行為：抽搐或對癲癇發作閾值的影響 心臟：心律失常（包括傳導改變） |
| 小鼠 | TDLo | 皮下 | 0.0549 | 周圍神經和感覺：局部麻醉 行為：鎮痛 |
| 兔子 | LDLo | 皮下 | 0.131 | 除致死劑量值外未報告詳情毒性作用 |
| 大鼠 | LD50 | 靜脈 | 0.080 | 行為：抽搐或對癲癇發作閾值的影響 |
| 大鼠 | LD50 | 靜脈 | 0.064 | 除致死劑量值外未報告詳情毒性作用 |
| 大鼠 | LDLo | 腹腔 | 0.250 | 心臟：其他變化 肺、胸：呼吸困難 |
| 大鼠 | LDLo | 靜脈 | 0.040 | 心臟：心律失常（包括傳導改變） |
| 大鼠 | TDLo | 腸外 | 0.040 | 心臟：心律失常（包括傳導改變） |
| 青蛙 | LDLo | 皮下 | 0.586 | 除致死劑量值外未報告詳情毒性作用 |
| 鴿子 | LDLo | 皮下 | 0.066 | 除致死劑量值外未報告詳情毒性作用 |
對於人類，1969 年報導的最低口服致死劑量為 28 μg/kg。
乌头碱（草乌、川乌）中毒在急诊及内科中常见，多因服用自制中药及自制药膳不当所致。[39]
它主要使迷走神经兴奋，对周围神经损害临床主要表现为口舌及四肢麻木，全身紧束感等，通过兴奋迷走神经而降低窦房结的自律性，引起異位起搏点的自律性增高而引起各心律失常，损害心肌。
临床作用 编辑
本品具有镇痛作用，临床上用于缓解癌痛，尤其适用于消化系统癌痛；外用时能麻痹周围神经末梢，产生局部麻醉和镇痛作用；有消炎作用，本品毒性极大，能兴奋麻痹感觉神经和中枢神经，兴奋心脏迷走神经，直接毒害心肌细胞。还有发汗作用。[來源請求]
参考文献 编辑
- ^ PubChem. Aconitine. pubchem.ncbi.nlm.nih.gov. [2022-08-24]. （原始内容于2021-09-29） （英语）.
- ^ 张晓 丁守汉. 自制“草乌酒”撂倒五个人. 温州都市报 (温州日报报业集团). 2007-08-03 [2022-08-24]. （原始内容于2022-08-24） （中文（中国大陆））.
- ^ 男子偷走广场上晒的草乌泡酒致身亡，原因竟是无知. 吴刚故事汇. 2022-07-09 [2022-08-24]. （原始内容于2022-08-24） （中文（中国大陆））.
- ^ 4.0 4.1 Chan TY. Aconite poisoning. Clinical Toxicology. April 2009, 47 (4): 279–285. PMID 19514874. S2CID 2697673. doi:10.1080/15563650902904407.
- ^ 在生物遺傳學，烏頭鹼不是真正的生物鹼，因為並非來源於氨基酸。烏頭鹼最終來源於異戊二烯，因此它在技術上是一種萜類化合物和偽生物鹼。
- ^ Shi Y, Wilmot JT, Nordstrøm LU, Tan DS, Gin DY. Total synthesis, relay synthesis, and structural confirmation of the C18-norditerpenoid alkaloid neofinaconitine. Journal of the American Chemical Society. September 2013, 135 (38): 14313–20. PMC 3883312 . PMID 24040959. doi:10.1021/ja4064958.
- ^ Aconitine. Sigma Aldrich. [22 July 2016].
- ^ Aconitine sc-202441 Material Safety Data Sheet (PDF). Santa Cruz Biotechnology. [2022-07-26]. （原始内容 (PDF)于2021-10-04）.
- ^ Dewick PM. Medicinal Natural Products. A Biosynthetic Approach 2nd. Wiley. 2002. ISBN 978-0-471-49640-3.
- ^ Desai HK, Joshi BS, Ross SA, Pelletier SW. Methanolysis of the C-8 Acetoxyl Group in Aconitine-Type Alkaloids: A Partial Synthesis of Hokbusine A. Journal of Natural Products. 1989, 52 (4): 720–725. doi:10.1021/np50064a009.
- ^ Pelletier SW, Mody NV. Chapter 1 The Structure and Synthesis of C19-Diterpenoid Alkaloids. Manske RH, Rodrigo R (编). The Alkaloids: Chemistry and Physiology 17. 1979: 4 [2022-07-26]. ISBN 9780080865416. doi:10.1016/S1876-0813(08)60296-1. （原始内容于2022-07-26）.
- ^ Pyroaconitine ChemSpider ID: 10211301. Chemspider. [2022-07-26]. （原始内容于2022-07-26）.
- ^ Gutser UT, Friese J, Heubach JF, Matthiesen T, Selve N, Wilffert B, Gleitz J. Mode of antinociceptive and toxic action of alkaloids of Aconitum spec. Naunyn-Schmiedeberg's Archives of Pharmacology. January 1998, 357 (1): 39–48. PMID 9459571. S2CID 21509335. doi:10.1007/pl00005136.
- ^ Benoit E. Mécanisme(s) d'action des neurotoxines agissant sur l'inactivation des canaux sodium activés par le potentiel de membrane [Mechanism of action of neurotoxins acting on the inactivation of voltage-gated sodium channels]. Comptes Rendus des Séances de la Société de Biologie et de Ses Filiales. 1998, 192 (3): 409–436. PMID 9759381 （法语）.
- ^ Okazaki M, Kimura I, Kimura M. Aconitine-induced increase and decrease of acetylcholine release in the mouse phrenic nerve-hemidiaphragm muscle preparation (pdf). Japanese Journal of Pharmacology. December 1994, 66 (4): 421–426 [2022-07-26]. PMID 7723217. doi:10.1254/jjp.66.421 . （原始内容于2022-07-26）.
- ^ Viberti F, Raveggi E. Aconitine: How Poisonous, How Harmful?. flipper e nuvola. [26 April 2017]. （原始内容于2022-07-26）.
- ^ Zhao PJ, Gao S, Fan LM, Nie JL, He HP, Zeng Y, Shen YM, Hao XJ. Approach to the biosynthesis of atisine-type diterpenoid alkaloids. Journal of Natural Products. April 2009, 72 (4): 645–9. PMID 19275222. doi:10.1021/np800657j.
- ^ 18.0 18.1 Wiesner K, Tsai TY, Huber K, Bolton SE, Vlahov R. Total synthesis of talatisamine, a delphinine type alkaloid. Journal of the American Chemical Society. July 1974, 96 (15): 4990–4992. doi:10.1021/ja00822a048.
- ^ 19.0 19.1 Wiesner K, Tsai TY, Nambiar KP. A new stereospecific total synthesis of chasmanine and 13-desoxydelphonine. Canadian Journal of Chemistry. 15 May 1978, 56 (10): 1451–1454. doi:10.1139/v78-237 .
- ^ 20.0 20.1 Wiesner K. Total synthesis of delphinine-type alkaloids by simple, fourth generation methods. Pure and Applied Chemistry. 1 January 1979, 51 (4): 689–703. doi:10.1351/pac197951040689 .
- ^ Peese KM, Gin DY. Efficient synthetic access to the hetisine C20-diterpenoid alkaloids. A concise synthesis of nominine via oxidoisoquinolinium-1,3-dipolar and dienamine-Diels-Alder cycloadditions. Journal of the American Chemical Society. July 2006, 128 (27): 8734–5. PMC 2610465 . PMID 16819859. doi:10.1021/ja0625430.
- ^ Shi Y, Wilmot JT, Nordstrøm LU, Tan DS, Gin DY. Total synthesis, relay synthesis, and structural confirmation of the C18-norditerpenoid alkaloid neofinaconitine. Journal of the American Chemical Society. September 2013, 135 (38): 14313–20. PMC 3883312 . PMID 24040959. doi:10.1021/ja4064958 （英语）.
- ^ Tang L, Ye L, Lv C, Zheng Z, Gong Y, Liu Z. Involvement of CYP3A4/5 and CYP2D6 in the metabolism of aconitine using human liver microsomes and recombinant CYP450 enzymes. Toxicology Letters. April 2011, 202 (1): 47–54. PMID 21277363. doi:10.1016/j.toxlet.2011.01.019.
- ^ Bertilsson L, Lou YQ, Du YL, Liu Y, Kuang TY, Liao XM, Wang KY, Reviriego J, Iselius L, Sjöqvist F. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clinical Pharmacology and Therapeutics. April 1992, 51 (4): 388–397. PMID 1345344. S2CID 42831017. doi:10.1038/clpt.1992.38.
- ^ 25.0 25.1 Beike J, Frommherz L, Wood M, Brinkmann B, Köhler H. Determination of aconitine in body fluids by LC-MS-MS. International Journal of Legal Medicine. October 2004, 118 (5): 289–93. PMID 15674996. S2CID 2490984. doi:10.1007/s00414-004-0463-2.
- ^ Tsukada K, Akizuki S, Matsuoka Y, Irimajiri S. [A case of aconitine poisoning accompanied by bidirectional ventricular tachycardia treated with lidocaine]. Kokyu to Junkan. Respiration & Circulation. October 1992, 40 (10): 1003–6. PMID 1439251 （日语）.
- ^ Ohno Y, Chiba S, Uchigasaki S, Uchima E, Nagamori H, Mizugaki M, Ohyama Y, Kimura K, Suzuki Y. The influence of tetrodotoxin on the toxic effects of aconitine in vivo (pdf). The Tohoku Journal of Experimental Medicine. June 1992, 167 (2): 155–8 [2022-07-26]. PMID 1475787. doi:10.1620/tjem.167.155 . （原始内容于2021-10-06）.
- ^ Fan YF, Xie Y, Liu L, Ho HM, Wong YF, Liu ZQ, Zhou H. Paeoniflorin reduced acute toxicity of aconitine in rats is associated with the pharmacokinetic alteration of aconitine. Journal of Ethnopharmacology. June 2012, 141 (2): 701–8. PMID 21930193. doi:10.1016/j.jep.2011.09.005.
- ^ Irving SN. Dangerous Properties of Industrial Materials Fifth. New York: Van Nostrand Reinhold Company Inc. 1979. ISBN 978-0-442-27373-6. LCCN 78-20812.
- ^ Macinnis P. It's True! You Eat Poison Every Day. Allen & Unwin. 2006: 80–81. ISBN 9781741146264.
- ^ Macinnis P. Poisons: From Hemlock to Botox and the Killer Bean of Calabar. Arcade Publishing. 2005: 25–26. ISBN 978-1-55970-761-9.
- ^ Parry LA, Wright WH. Some Famous Medical Trials. Beard Books. 2000: 103. ISBN 978-1-58798-031-2.
- ^ . Novaya Gazeta. 2010-05-06 [2013-04-08]. （原始内容存档于2010-05-30） （俄语）.
- ^ Poisoning in west London in 2009. BBC TV News. 2010-02-10 [2022-07-26]. （原始内容于2020-05-27）.
- ^ Ovid, Metamorphoses, 1.147
- ^ Jensen, Jeff. Twin Peaks recap: 'The Return: Part 13'. Entertainment Weekly (Meredith Corporation). 7 August 2017 [4 May 2020]. （原始内容于2022-04-19）.
Clark offered to sell him Aconitine, a toxin with a rich literary history.
- ^ Aconite. Drugs.com. 9 August 2019 [23 June 2020]. （原始内容于2022-07-26）.
- ^ 38.0 38.1 RTECS. Oct 2011.
- ^ 龙明洁. 农妇误将外用药酒给人饮 好心酿悲剧被判刑. 正义网. [2011-12-05]. （原始内容于2017-05-06）.