benzoylmesaconine and benzoylaconine

Fuzi, the lateral roots of Aconitum carmichaelii Debx, plays an irreplaceable role in treating Yang deficiency and cold coagulation syndromes. However, Fuzi has a narrow margin of safety since its pharmacological constituents, Aconitum alkaloids, have potential cardiotoxicity and neurotoxicity. The current quality markers (Q-markers) for the control of Fuzi's efficacy and toxicity are 3 monoester-diterpenoid alkaloids, namely, benzoylaconine (BAC), benzoylhypaconine and benzoylmesaconine (BMA) and 3 diester-diterpenoid alkaloids, namely, aconitine (AC), hypaconitine and mesaconitine (MA). However, mounting evidence indicates that the current 6 Q-markers may not be efficacy- or toxicity-specific enough for Fuzi.. The aim of this study was to explore and evaluate efficacy- or toxicity-specific potential quality markers (PQ-markers) of Fuzi.. PQ-markers were explored by analyzing 30 medicinal samples and alkaloids exposed in mouse. Pharmacokinetics of PQ-markers on C57BL/6J mice were determined. Anti-inflammatory effects of PQ-markers were evaluated by λ-carrageenan-induced paw edema model and lipopolysaccharide-induced RAW264.7 cell inflammatory model, while analgesic effects were assessed by acetic acid-induced pain model and Hargreaves test. Cardiotoxicity and neurotoxicity of PQ-markers were assessed by histological and biochemical analyses, while acute toxicity was evaluated by modified Kirschner method.. Seven PQ-markers of Fuzi were found after in vitro and in vivo explorations. Among them, NE, FE and SE were found to be more efficacy-specific than BMA, and 10-OH MA was as toxicity-specific as MA.

Topics: Aconitine; Aconitum; Alkaloids; Analgesics; Animals; Anti-Inflammatory Agents; Chromatography, High Pressure Liquid; Diterpenes; Drugs, Chinese Herbal; Mice; Mice, Inbred C57BL; Plant Roots

Processed aconite root (PA), the root of Aconitum carmichaeli (Ranunculaceae), is a crude drug used in traditional Chinese or Japanese kampo medicine to treat pain associated with coldness. In our previous study, PA and its active ingredient, neoline, alleviated oxaliplatin-induced peripheral neuropathy in mice.. The present study investigated the effects of PA on a murine peripheral neuropathy model induced by intraperitoneal injection of paclitaxel and partial ligation of the sciatic nerve (Seltzer model), and identified its active ingredients.. PA powder (1 g/kg/day) was orally administered, and either neoline or benzoylmesaconine (10 mg/kg/day) was subcutaneously injected into the murine model. Mechanical hyperalgesia was evaluated via the von Frey filament method. PA extract was orally administered to rats; blood samples were chronologically collected, and the plasma concentrations of Aconitum alkaloids were measured. The contents of Aconitum alkaloids in commercial PA products were also measured.. PA extract and neoline significantly attenuated the mechanical hyperalgesia induced by either paclitaxel or partial ligation of the sciatic nerve in mice. In the plasma samples of rats treated with PA extract, higher concentrations of benzoylmesaconine and neoline were apparent among Aconitum alkaloids. The contents of benzoylmesaconine and neoline varied among PA products with different processing procedures. Subcutaneous injection of benzoylmesaconine did not attenuate the hyperalgesia induced by each paclitaxel, partial ligation of the sciatic nerve, or oxaliplatin in mice.. The present results indicate that PA and its active ingredient, neoline, are promising agents for the alleviation of neuropathic pain. Neoline can be used as a marker compound to determine the quality of the PA products for the treatment of neuropathic pain.

Topics: Aconitine; Aconitum; Analgesics; Animals; Antineoplastic Agents, Phytogenic; Hyperalgesia; Male; Mice; Neuralgia; Paclitaxel; Peripheral Nerve Injuries; Plant Roots; Rats, Wistar; Sciatic Nerve

In this study, we developed a method using ultra high-performance liquid chromatography coupled with electrospray ionisation tandem mass spectrometry for determining the contents of chlorogenic acid, atractylenolide I, atractylenolide III, benzoylaconine, benzoylmesaconine, benzoylhypaconine, glycyrrhizic acid, glycyrrhetic acid, liquiritigenin, and cinnamic acid in Yinchenzhufu decoction, a classic traditional Chinese medicine prescription. Separation was performed on a C18 column (4.6mm i.d.×250mm, 5μm) and achieved with good linearity (r(2)>0.9984) within 35min. Gradient elution was applied using a mobile phase of 0.05% acetic acid/acetonitrile. The analytes were quantified on an LCQ ion trap mass spectrometer in electrospray ionisation full-scan mode. Variations in the intra- and inter-day precision of all analytes were below 4.57%, and the accuracy was evaluated by a recovery test within the range of 97.88-102.25%. The method successfully quantified the 10 compounds in five sample batches of Yinchenzhufu decoction, and the results show that the method is accurate, sensitive, and reliable.

Topics: Aconitine; Chlorogenic Acid; Chromatography, High Pressure Liquid; Cinnamates; Drugs, Chinese Herbal; Flavanones; Glycyrrhetinic Acid; Glycyrrhizic Acid; Lactones; Medicine, Chinese Traditional; Sesquiterpenes; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

In this study, we explored the rationality of processing methods and mechanism of Aconiti Lateralis Radix (Fuzi) through comparing the chemical contents of diester alkaloids (DAs) and monoester alkaloids (MAs) in the raw material of Fuzi and its processed products. The results showed that the toxicity potency of MAs is at least lower than 1/64 to 1/180 of the toxicity potency of DAs. The contents of DAs in processed Fuzi decreased to 1/76.5 to 1/38.3 of the value of raw Fuzi. The contents of MAs in processed Fuzi significantly increased by 4.6 to 5.2 fold or basically the same as that of the raw Fuzi. The values of MAs/DAs of processed Fuzi were enhanced by 30 to 390 fold of the raw Fuzi. It was found that the contents of DAs were insignificantly different between "Wu dan fu pian" (steaming or stir-frying without Danba) and "Dan fu pian" (steaming or stir-frying with Danba). The result suggested that the abilities of "eliminating toxicity" of different processing methods were equivalent at all. In contrast, the contents of MAs contained in "Wu dan fu pian" were of 5.3 to 8.7 fold higher than the values in "Dan fu pian". This result suggested the processing method by steaming or stir-frying without Danba might have better effect for "conserving property" than the method processed with Danba stipulated by China Pharmacopoeia. We believe that the new processing method without Danba can be recommended in further application due to it offers a simple procedure and it will not introduce inorganic impurities in the products.

Topics: Aconitine; Aconitum; Animals; Chromatography, High Pressure Liquid; Cluster Analysis; Drugs, Chinese Herbal; Male; Rats; Rats, Sprague-Dawley; Technology, Pharmaceutical

Radix Aconiti Lateralis (Fuzi in Chinese, derived from the lateral roots of Aconitum Carmichaeli Debx.) is widely used for the treatment of heart failure, internal cold, arthralgia, diarrhea and edema for thousands of years. It was usually prescribed in combination with Rhizoma Zingiberis (Ganjiang in Chinese, derived from the dry rhizome of Zingiber officinale Rosc.) to decrease toxicity and increase efficacy.. In order to investigate the influence of Rhizoma Zingiberis on pharmacokinetics of six Aconitum alkaloids, i.e. aconitine (AC), hypaconitine (HA), mesaconitine (MA), benzoylaconine (BAC), benzoylhypaconine (BHA) and benzoylmesaconine (BMA), in Fuzi-Ganjiang herb couple, the comparative pharmacokinetics of six Aconitum alkaloids after oral administration of Fuzi and Fuzi-Ganjiang aqueous extract was carried out.. A sensitive, specific and rapid LC-MS/MS method was developed to determine the six analytes in plasma. Then the rats were randomly divided into two groups and orally administered with Fuzi and Fuzi-Ganjiang aqueous extract. At designated time points after oral administration, the concentrations of the six Aconitum alkaloids in rat plasma were determined, and main pharmacokinetic parameters were investigated using 3P97 (Practical Pharmacokinetics Program Version 1.0).. Comparing with Fuzi group, both T1/2 and AUC0-t of AC and HA decreased (P<0.05), while T1/2, AUC0-t and Cmax of BAC, BHA increased (P<0.05) in Fuzi-Ganjiang group, which indicated that Ganjiang could promote the elimination of AC and HA and enhance the absorption of BAC, BHA and BMA.. The differences of pharmacokinetics of Aconitum alkaloids in rat plasma could support those of pharmacologics and toxicity in previous reports between Fuzi and Fuzi-Ganjiang herb couple. The results might be helpful in explaining the mechanism of combination of Fuzi-Ganjiang to decrease toxicity and increase efficacy.

Topics: Aconitine; Aconitum; Alkaloids; Animals; Area Under Curve; Chromatography, High Pressure Liquid; Diterpenes; Drugs, Chinese Herbal; Male; Mass Spectrometry; Medicine, Chinese Traditional; Plant Extracts; Random Allocation; Rats; Rats, Sprague-Dawley; Rhizome; Tandem Mass Spectrometry; Zingiber officinale

A rapid, specific and sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) method was developed for simultaneous quantitation of six Aconitum alkaloids, i.e. aconitine (AC), mesaconitine (MA), hypaconitine (HA), benzoylaconine (BAC), benzoylmesaconine (BMA) and benzoylhypaconine (BHA) in human plasma collected from 18 healthy volunteers after intravenous drop infusion of "SHEN-FU" injectable powder in three different dosages. Lappaconitine was selected as the internal standard (IS). LC/MS/MS system coupled with an electrospray ionization (ESI) source was performed in multiple-reaction monitoring (MRM) mode. The transitions of the Aconitum alkaloids executed as following: m/z 646.3-->586.0 for AC; m/z 632.4-->573.1 for MA; m/z 616.2-->556.1 for HA; m/z 604.2-->104.8 for BAC; m/z 590.1-->104.8 for BMA; m/z 574.1-->104.8 for BHA; m/z 585.2-->161.8 for IS. Sample preparation was performed with solid-phase extraction (SPE) on a 1 mL HLB cartridge prior to analysis. The separation was applied on a Waters C(18) column (1.7 microm, 2.1 mm x 100 mm) and a gradient elution of methanol and 0.1% formic acid-water was used as mobile phase. The retention time was less than 4.5 min. The concentrations ranged from 0.1 to 1000 ng/mL for all six Aconitum alkaloids and showed a good linearity with the correlation coefficient (r(2)) >0.995. The validated method was employed to simultaneous quantitation and successfully used for the first time for the pharmacokinetic evaluation of the six Aconitum alkaloids after intravenous drop administration of "SHEN-FU" injectable powder in phase I clinical trial.

Topics: Aconitine; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Humans; Medicine, Chinese Traditional; Sensitivity and Specificity; Tandem Mass Spectrometry

To separate and quantitatively determine six alkaloids: aconitine, mesaconitine, hypaconitine, beiwutine, benzoylaconine and benzoylmesaconine in the Chinese traditional medicine Radix Aconiti Lateralis Preparata (Fuzi).. A RP-ion-pair HPLC method was established. An AichromBond-1 C18 column was used at a column-temperature of 35 degrees C. The mobile phase was CH3CN5 mmol x L(-1) NaH2PO4(50:50) containing 7 mmol x L(-1) SDS at a flow-rate of 1.0 mL x min(-1). The detector was set at UV 235 nm.. These six alkaloids can be completely separated and determined quantitatively.. This method is accurate and suitable for the determination of six alkaloids in Fuzi.

Topics: Aconitine; Aconitum; Alkaloids; Chromatography, High Pressure Liquid; Plant Roots; Plants, Medicinal