A systematic review of pharmacological activities, toxicological mechanisms and pharmacokinetic studies on Aconitum alkaloids

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.

Microcalorimetry studies of the antimicrobial actions of Aconitum alkaloids

The metabolic activity of organisms can be measured by recording the heat output using microcalorimetry. In this paper, the total alkaloids in the traditional Chinese medicine Radix Aconiti Lateralis were extracted and applied to Eschenchia coil and Staphylococcus aureus. The effect of alkaloids on bacteda growth was studied by microcalorimetry. The power-time curves were plotted with a thermal activity monitor （TAM） air isothermal microcalorimeter and pa- rameters such as growth rate constant （p）, peak-time （Trn）, inhibitory ratio （I）, and enhancement ratio （E） were cal- culated. The relationships between the concentration of Aconitum alkaloids and p of E. coil or S. aureus were discussed. The results showed that Aconitum alkaloids had little effect on E. coil and had a potentially inhibitory effect on the growth of S. aureus.

New C_(20)-diterpenoid alkaloids from Aconitum sinomontanum

Two new denudatine-type C20-diterpenoid alkaloids, named sinomontanidines A （1） and B （2）, were isolated from the roots ofAconitum sinomontanum Nakai. Their structures were elucidated by extensive analysis of 1D, 2D NMR, and MS data.

Four new diterpenoid alkaloids with antitumor effect from Aconitum nagarum var. heterotrichum

Four new diterpenoid alkaloids,nagaconitines A-D（1-4）,were isolated from the roots of Aconitum nagarum var.heterotrichum.Their structures were elucidated as 8-（4＇-hydroxylbutyryl） aconitine（1）,15-oxo-13-deoxyludaconitine（2）,15-hydroxyldelphisine（3）,and 14-hydroxyl-2- acetoxyspiradine C（4）based on extensive UV,IR,MS,1D NMR and 2D NMR analyses.Compounds 3-4 showed inhibition of cancer cell line SK-OV-3 with 31%（IC_（50） 43.78 μmol/L） and 24%（IC_（50） 32.14 μmol/L）,respectively.

Qualitative and Quantitative Analysis of Drug Interactions： Fritillary Mediating the Transport of Alkaloids in Caco-2 Cells by P-Glycoprotein

Ultra performance liquid chromatographic-electrospray ionization-mass spectrometry（UPLC-ESI-MS） was used to investigate the potential interaction between selected ingredients of Aconitum and fritillary. The efflux ratios of 14-benzoylmesaconine（BM）, 14-benzoylaconine（BC）, 14-benzoylhypaconine（BH）, mesaconitine（MA）, aco- nitine（AC） and hypaconitine（HA） was 11.16, 12.53, 11.69, 12.8, 11.03 and 6.15, respectively, and the secretion of them was inhibited by Veraparnil, which means they are the substrates of permeability-glycoprotein（P-gp）. The transport of Aconitum alkaloids extract through a Caco-2 cell monolayer was determined in the absence and presence of fritillary extract. And the fritillary extract increased the absorption of Aconitum alkaloids. Peimine（PE） and peimi- nine（PEN） in fritillary increased the absorption of pure Aconitum alkaloids. The transport of digoxin was respectively enhanced by PE and PEN, which means they are the inhibitors of P-gp. PEN showed more effective inhibition than PE at the same concentration. The in vitro data suggest that the compounds such as fritillary present in alkaloids were able to inhibit the P-gp activity and lead modifying the transport of alkaloids.

Non-thermal plasma treatment of Radix aconiti wastewater generated by traditional Chinese medicine processing

The wastewater effluent from Radix aconiti processing, an important step in the production processes of traditional Chinese medicine（TCM）, is a type of toxic wastewater and difficult to treat. Plasma oxidation methods have emerged as feasible techniques for effective decomposition of toxic organic pollutants. This study examined the performance of a plasma reactor operated in a dielectric barrier discharge（DBD） to degrade the effluent from R. aconiti processing. The effects of treatment time, discharge voltage, initial pH value and the feeding gas for the reactor on the degradation of this TCM wastewater were investigated. A bacterium bioluminescence assay was adopted in this study to test the toxicity of the TCM wastewater after non-thermal plasma treatment. The degradation ratio of the main toxic component was 87.77% after 60 min treatment with oxygen used as feed gas and it was 99.59% when the initial p H value was 8.0. High discharge voltage and alkaline solution environment were beneficial for improving the degradation ratio. The treatment process was found to be capable of reducing the toxicity of the wastewater to a low level or even render it non-toxic. These experimental results suggested that the DBD plasma method may be a competitive technology for primary decomposition of biologically undegradable toxic organic pollutants in TCM wastewater.

Unprecedented C_(19)-diterpenoid alkaloid glycosides from an aqueous extract of“fu zi”:Neoline 14-O-L-arabinosides with four isomeric L-anabinosyls

Four structurally unprecedented aconitane-type C_（19）-diterpenoid alkaloid glycosides with isomeric arabinosyls, named aconicarmichosides A–D（1–4）, were isolated from an aqueous extract of ＂fu zi＂, the lateral roots of Aconitum carmichaelii. Their structures were determined as neoline 14-O-a-and 14-O-b-L-arabinopyranosides（1 and 2） and 14-O-a-and 14-O-b-L-arabinofuranosides（3 and 4）, by spectroscopic and chemical methods including 2D NMR experiments and acid hydrolysis. Compounds 1–4 represent the first examples of glycosidic diterpenoid alkaloids.

A minor arcutine-type C20-diterpenoid alkaloid iminium constituent of“fu zi”

A rare arcutine-type C_（20）-diterpenoid alkaloid, named aconicarmicharcutinium A and obtained as hydroxide（1） and trifluoroacetate（1a）, was characterized as a minor constituent of ＂fu zi＂（the lateral roots of Aconitum carmichaelii）. The structures of 1 and 1a were elucidated by comprehensive analysis of spectroscopic data including^（19）F and 2D NMR experiments. Compounds 1 and 1a represent the first examples of the arcutine-type C_（20）-diterpenoid alkaloid iminium.