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The tubers and roots of Aconitum (Ranunculaceae) are widely used as heart medicine or analgesic agents for the treatment of coronary heart disease, chronic heart failure, rheumatoid arthritis and neuropathic pain since ancient times. As a type of natural products mainly extracted from Aconitum plants, Aconitum alkaloids have complex chemical structures and exert remarkable biological activity, which are mainly responsible for significant effects of Aconitum plants. The present review is to summarize the progress of the pharmacological, toxicological, and pharmacokinetic studies of Aconitum alkaloids, so as to provide evidence for better clinical application. Research data concerning pharmacological, toxicological and pharmacokinetic studies of Aconitum alkaloids were collected from different scientific databases (PubMed, CNKI, Google Scholar, Baidu Scholar, and Web of Science) using the phrase Aconitum alkaloids, as well as generic synonyms. Aconitum alkaloids are both bioactive compounds and toxic ingredients in Aconitum plants. They produce a wide range of pharmacological activities, including protecting the cardiovascular system, nervous system, and immune system and anti-cancer effects. Notably, Aconitum alkaloids also exert strong cardiac toxicity, neurotoxicity and liver toxicity, which are supported by clinical studies. Finally, pharmacokinetic studies indicated that cytochrome P450 proteins (CYPs) and efflux transporters (ETs) are closely related to the low bioavailability of Aconitum alkaloids and play an important role in their metabolism and detoxification in vivo.
Subject(s)
Aconitum/chemistry , Alkaloids/toxicity , Biological Availability , Phytochemicals/toxicity , Plant Roots/chemistryABSTRACT
OBJECTIVE:To establish HPLC-quadrupole/electrostatic field orbitrap high resolution mass spectrometry for rapid determination of aconitine,mesaconitine,hypaconitine,benzoylaconitine,benzoylmesaconine and benzoylhypacoitine in rat plasma. METHODS:Internal standard lappaconitine was added into plasma sample,and methanol precipitated protein was used for pretreatment. HPLC-quadrupole/electrostatic field orbitrap high resolution mass spectrometry was adopted. HPLC condition was as follows as Sinochrom ODS-BP C18column,mobile phase consisted of acetonitrile-1% formic acid solution(50:50,V/V),the flow rate of 0.6 mL/min,sample size of 10 μL,column temperature of 25 ℃,automatic sampler temperature of 4 ℃. Mass spectrum scanning mode was full ion monitoring model,positive ion acquisition,mass charge ratios(m/z)of ion were 646.32(aconitine), 632.30(mesaconitine),616.31(hypaconitine),604.31(benzoylaconitine),590.29(benzoylmesaconine),574.30(benzoylhypacoitine), 585.31(internal standard). Six male Wistar rats were collected and given single dose of total alkaloid extract of Aconitum carmichaeli(4 mg/kg)intragastrically. Blood samples were collected before medication(0 h)and 0.5,0.75,1.25,1.5,2,4,6, 8,10,24 h after medication. Plasma concentration was determined and pharmacokinetic parameters were calculated by using PK-Solver V2.0 software. RESULTS:The linear range of 6 kinds of aconitum alkaloids in plasma were 0.1-10 μ g/L(r>0.992). The limit of quantitation was 0.1 μ g/L. Average recovery was higher than 75%,RSDs of intra-day and inter-day,matrix effects,stability test were all lower than 15%. The tmaxof 6 kinds of aconite alkaloids were about 1.2 h;t1/2were about 10 h;cmaxof monoestertype aconite alkaloids were higher than those of diester-type aconite alkaloids. CONCLUSIONS:Established HPLC-quadrupole/electrostatic field orbitrap high resolution mass spectrometry is accurate,sensitive,simple and rapid, and can be used for plasma concentration monitoring of 6 kinds of aconitum alkaloids.
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Objective: To investigate the hydrolysis conversion rate of alcohol amine-diterpene alkaloids from aconitum alkaloids, hydrolyze aconitum alkaloids reference substance, calculate the amount of alcohol amine-diterpene alkaloids in the hydrolysis solution by the hydrolysis conversion rate, which is used as the amount of alcohol amine-diterpene alkaloids reference substance, and establish a content determination method for aconine, hypaconitine and aconine in Aconiti radix cocta.Methods: Through controlling the hydrolysis conditions of aconitine, hypaconitine and mesaconitine, aconine, hypaconitine and aconine were obtained.The determination was performed on an Agilent ZORBAX Extend-C18 RRHT(2.1 mm×50 mm,1.8 μm) column with the mobile phase consisting of methanol(A)-water(B containing 0.1% formic acid and 2.5 mmol·L-1 ammonium acetate) with gradient elution by HPLC-QTOF-MS.The flow rate was 0.21 ml·min-1.The column temperature was 30 ℃.MS instrument was equipped with an ESI+ ion source.Results: Under the hydrolysis conditions of this study, the conversion rate of aconine from aconitine was 99.64%;the conversion rate of hypaconitine from hypaconine was 99.94%;the conversion rate of mesaconitine from mesaconine was 99.57%.The HPLC-QTOF-MS methodological investigation showed the 3 kinds of alcohol amine-diterpene alkaloids were with good linearity (r>0.999 1).The RSD of the precision, repeatability and stability tests were less than 5%.The average recoveries were within the range of 99.43%-100.10%.Conclusion: The validated method is simple, specific, reliable and reproducible.In the absence of reference substance, it can be used for the quality control of the herbs of Aconitum L.species.
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Objective To establish a HPLC-MS method for determination of aconitum alkaloids in biological samples. Methods The aconitum alkaloids were extracted from the whole blood by using acetonitrile-methanol (5:1 v/v) and then analyzed using HPLC-MS in multiple reaction monitoring (MRM) mode with positive ionization. The analytical column was Agilent Zorbax SB C18 (2.1mm×50mm, 1.8μm)and the mobile phase were water containing 0. 1 % formic acid : acetonitrile (60 : 40 v/v) in isocratic elution. Results The retention time of detection of the aconitine, hypaconitine and mesaconitine were 0.73 min, 0.77 min and 0.63 min, and the precursor product ion combinations of m/z 646.4 → 586.4, 616.1 → 556.5 and 632.4 → 572.1 were used for quantitative analysis, respectively. Calibration curve was linear within the range of 0.1-250 ng/mL with the LOD was 0.1ng/mL, and the coefficient of variation (CV) less than 5.42 % (n=6). The extraction recoveries of aconitine in blood were more than 90 %.Conclusion The results demonstrated that the present method was reliable and robust for natural drugs.
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Shenfu Injection (SFI) is a well-defined Chinese herbal formulation that is obtained from red ginseng and processed aconite root. The main active constituents in SFI are ginsenosides and aconitum alkaloids. In this work, ginsenosides (ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rc) and aconitum alkaloids (benzoylmesaconine and fuziline) were used as the index components to explore the pharmacokinetic behavior of SFI. A selective and sensitive HPLC-MS/MS method was developed for the quantification of ginsenosides and aconitum alkaloids in dog plasma and was used to characterize the pharmacokinetics of the five index components after intravenous drip of three different dosages of SFI in beagle dogs. The pharmacokinetic properties of the index components were linear over the dose range of 2-8 mL/kg.
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Objective To evaluate the effect of lappaconitine on renal ischemia-reperfusion (I/R) injury in mice.Methods Thirty-six male Wistar rats,weighing 180-220 g,were randomly divided into 3 groups (n=12 each) using a random number table:sham operation group (group S),group I/R and lappaconitine group (group LA).Renal I/R was induced by occlusion of the left renal pedicle for 45 min with atraumatic microclips followed by reperfusion,and the right kidney was removed after atraumatic microclips were released.At 30 min before reperfusion,lappaconitine 4 mg/kg was injected intraperitoneally in group LA,and normal saline 2 ml was given in S and I/R groups.In group S,the left renal pedicle was only isolated.At 5 and 24 h of reperfusion,blood samples were taken from the inferior vena cava for determination of serum creatinine (Cr) and blood urea nitrogen (BUN) concentrations,and kidney specimens were obtained for histopathologic examination (with light microscope) and for determination of the expression of cyclooxygenase-2 (COX-2) and matrix metalloproteinase-2 (MMP-2) in renal tissues (by immunohistochemistry).Results Compared with group S,the serum Cr and BUN concentrations were significantly increased,and the expression of COX-2 and MMP-2 in renal tissues was up-regulated at 5 and 24 h of reperfusion in I/R and LA groups.Compared with group I/R,the serum Cr and BUN concentrations were significantly decreased,the expression of COX-2 and MMP-2 in renal tissues was down-regulated at 5 and 24 h of reperfusion and histopathologic changes were reduced in group LA.Conclusion Lappaconitine can attenuate renal I/R injury through inhibiting the expression of COX-2 and MMP-2 in rats.
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Objective: To analyze the effect of starch composition on the dissolution of small molecular alkaloids in Aconiti Radix when co-decocted with medicines rich in starch, and to explore the mechanism of the effect of starch on alkaloids. Methods: RRLC-Q- TOF-MS was used to analyze the effect of starch on the dissolution of alkaloids in the decoctions. HPLC-UV was applied to determine the content of alkaloids in the decoctions of starches with alkaloids, and analysis of variance and partial least square method were used to analyse the difference. Results: The dissolution of alkaloids in Aconiti Radix, including the diester-, monoester-, and amine- diterpenoid alkaloids, wsa obviously decreased when co-decocted with starch, especially the monoester- and amine-diterpenoid alkaloids co-decocted with Pinelliae Rhizoma, Ampelopsis Radix, starch of Pinelliae Rhizoma, starch of Ampelopsis Radix, and normally sold starch, while the content of diester-diterpenoid alkaloids was increased when co-decocted with starch-removed Pinelliae Rhizoma and Ampelopsis Radix. When co-decocted directly with starch, free alkaloids in water decoction was decreased compared with the decoction without starch. Conclusion: Starch could inhibit the dissolution of alkaloids in Aconiti Radix in the decoction. Free Aconitum alkaloids could be integrated by the starch, which could finally affect their content in decoction.
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Aconltium plants are a group of important poisonous plants in the Ranunculaeeae family of Angiosperm subphylum.and one of the earliest recorded poisonous plants in China as well.In their tubers(root)have hypertoxic Aconitium alkaloids,which belong to the group of diesterditerpene alkaloids.It is repeatedly reported in China that aconitine poisoning,and even death from aconitine poisoning,caused by the individual differences in pharmaceutical tolerance of aconitine,taking the wrong medicine or inadequate dosage,or put in the poison by homicide.At present,the research on aconitine is mainly limited to clinical treatment,but lack of research on toxicity mechanism of aeonitine.This paper reviews some progress relating to the toxicological mechanisms of this kind of alkaloid.
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Objective To compare the extraction methods of cellulose enzyme,semi-bionic and alcohol reflux for the impact of aconitine and aconitum alkaloids yields,and to optimize the extraction method. Methods The optimum condition of enzymatic extraction has been obtained by orthogonal test and compared with semi-bionic and alcohol reflux extraction by taking the contents of aconitine and aconitum alkaloids as indexes.Results The optimum extraction conditions were as follows:the temperature was 45℃, pH value was 4.5,the amount of cellulose enzyme was 8 mg/g,the extracting time was 5 h and the extraction rate of aconitine was 0.002 447%,aconitum alkaloids was 0.244 410%.The extraction rates of aconitine and aconitum alkaloids of semi-bionic extraction were 0.001 735%and 0.189 340%,respectively. The extraction rates of aconitine and aconitum alkaloids of alcohol reflux extraction were 0.001 869% and 0.200 720%respectively.The enzymatic extraction has a significant advantage.Conclusion The enzymatic extraction significantly improve the extraction rates of aconitine and aconitum alkaloids,it could be applied in practice.
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AIM:To establish a method for detecting three aconitum alkaloids(aconitine,mesaconitine,hy-paconitine) in Zhentong Huoluo Tincture(Radix Aconiti,Radix Aconiti kusnezoffii,Radix et Rhizoma Rhei,Rhizoma Pinelliae,Rhizoma Arisaematis ect.).METHODS:A ZOBAX Extend-C_ 18(250 mm?4.6 mm,5 ?m) column was used to determine the aconitum alkaloids in Zhentong Huoluo Tincture.The mobile was gradient elution,0.1% die-thylamine(adjust pH 9.0 with phosphoric acid) as mobile A;0-20 min A∶B(63∶37),20-45 min A∶B(63∶55∶37→45),at the rate of 1 mL/min.The temperature of column was 30 ℃,and the wavelength was at 232 nm.RESULTS:The linearity of the aconitine in 9.74 ng-974 ng was 0.999 9;that of the mesaconitine in 23.86-2 386 ng was 0.999 9 and that of the hypaconitine in 29.94 ng-2 994 ng was 0.999 9.The RSD of precision for these three were 1.50%、0.68% and 0.49%,respectively.The average recoveries and its RSD were 100.2%(RSD 3.2 %)、102.9%(RSD 2.2%) and 98.2(RSD 2.0%),respectively for aconitin,mesaconitine and hypaconitine.The reproducibilities were all less than 2.0%,and the sample solution was stable in 24 h.CONCLUSION:The method is simple,accurate and has good stability,can be used for the quantity control in the product of Zhentong Huoluo Tincture.