Legal Medicine
·
2023
·
IF 1.5
Shan Zhang,Shunqin Chen,Faze Zhu,Aimin Wang,Bing Xia,Jie Wang,Jiang Huang,Yubo Liu,Peng Luo
Toxic alkaloids are typically found in herbal medicines and have strong pharmacological effects and a broad therapeutic spectrum. On the other hand, toxic alkaloids exert toxicological activities in vivo ; as such they have a narrow therapeutic window and can induce poisoning due to incorrect dose or misuse. In this view, there is an urgent need to develop a rapid and sensitive assay to detect these toxic alkaloids. This study developed a method for determining five common toxic alkaloids in blood, including brucine, strychnine, aconitine, mesaconitine, and hypaconitine using ultra-high liquid chromatography-tandem quadrupole/linear ion trap mass spectrometry (QTRAP UPLC–MS/MS). The analytes in this investigation were extracted with ether and detected using multiple reaction monitoring (MRM)-information-dependent acquisition (IDA)-enhanced product ion (EPI) scanning modes. SKF 525A served as the internal standard (IS). The approach demonstrated excellent linearity, with a correlation coefficient (R) > 0.9964, and satisfactory sensitivity, with the limit of detection (LOD) of 0.31 ∼ 3.26 ng/mL and a limit of quantification (LOQ) of 1.13 ∼ 11.52 ng/mL. The extraction recovery (ER) was 78.8 ∼ 116.2%, the matrix effect (ME) was −12.3 ∼ 21.2%, and the method accuracy was 0.8 ∼ 12.8%. In addition, the intra-day precision and the inter-day precision (RSD) were 0.7% ∼ 7.4% and 0.4% ∼ 13.5%, respectively. The developed approach is sensitive and efficient, and offer significant application prospect in clinical monitoring and forensic detection of poisoning.
研究领域:
分析化学
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法医学
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临床毒理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2021
·Vol. 73
·期 4
·535-544
·
IF 3.765
Yang Zemin,Lin Yanke,Su Chong,Wang Shuai,Gao Lu,Lin Jingpan,Wang Zhigang,Wu Baojian
ObjectivesIdentifying drugs with time-varying efficacy or toxicity, and understanding the underlying mechanisms would help to improve treatment efficacy and reduce adverse effects. In this study, we uncovered that the therapeutic effect of Fuzi (the lateral root of Aconitum carmichaelii Debeaux) depended on the dosing time in mice with adenine-induced chronic kidney disease (CKD).MethodsThe Fuzi efficacy was determined by biomarker measurements [i.e. plasma creatinine (CRE), blood urea nitrogen (BUN) and urinary N-acetyl-β-D-glucosaminidase (NAG)], as well as inflammation, fibrosis and histological analyses. Circadian regulation of Fuzi pharmacokinetics and efficacy was evaluated using brain and muscle Arnt-like protein-1 (Bmal1)-deficient (Bmal1−/−) mice.Key findingsThe Fuzi efficacy was higher when the drug was dosed at ZT10 and was lower when the drug was dosed at other times (ZT2, ZT6, ZT14, ZT18 and ZT22) according to measurements of plasma CRE, BUN and urinary NAG. Consistently, ZT10 (5 PM) dosing showed a stronger protective effect on the kidney (i.e. less extensive tubular injury) as compared to ZT22 (5 AM) dosing. This was supported by lower levels of inflammatory and fibrotic factors (IL-1β, IL-6, Tnf-α, Ccl2, Tgfb1 and Col1a1) at ZT10 than at ZT22. Pharmacokinetic analyses showed that the area under the curve (AUC) values (reflective of systemic exposure) and renal distribution of aconitine, hypaconitine and mesaconitine (three putative active constituents) for Fuzi dosing at ZT10 were significantly higher than those for herb dosing at ZT22, suggesting a role of circadian pharmacokinetics in Fuzi chronoefficacy. Drug efficacy studies confirmed that aconitine, hypaconitine and mesaconitine possessed a kidney-protecting effect. In addition, genetic knockout of Bmal1 in mice abolished the time-dependency of Fuzi pharmacokinetics and efficacy. This reinforced the existence of chronoefficacy for Fuzi and supported the role of circadian pharmacokinetics in Fuzi chronoefficacy.ConclusionsThe efficacy of Fuzi against CKD depends on the dosing time in mice, which is associated with circadian pharmacokinetics of the three main active constituents (i.e. aconitine, hypaconitine and mesaconitine). These findings highlight the relevance of dosing time in the therapeutic outcomes of herbal medicines.
研究领域:
药理学
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生物钟学
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中医
·
肾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2018
·
IF 3.115
Min Zhang,Ying Peng,Mengyue Wang,Beibei Gao,Lijuan Zhao,Xiaobo Li
Ethnopharmacological relevance In traditional Chinese medicine , processed aconite root (lateral root of Aconitum carmichaelii Debx.) is used as the principle herb of the Si-Ni decoction (SND) formula due to its cardiotonic effect, while its cardiotoxicity and neurotoxicity caused by diester and monoester diterpenoid alkaloids are reduced by compatibility of dried ginger and honey-processed liquorice in SND. Aim of the study To investigate the detoxification of processed aconite root by compatibility of SND from the perspective of intestinal absorption with metabolism in intestinal bacteria . Materials and methods Decoctions of processed aconite root (AD), processed aconite root and honey-processed liquorice (ALD), and SND with the same amount of each herb were prepared, then were incubated in human intestinal bacteria juice (IBJ) in vitro for different durations. Bidirectional transmembrane transports of these decoctions and their IBJ-incubated decoctions were conducted on Caco-2 monolayers. Correlation between efflux ratios changes of benzoylmesaconine, benzoylaconine, benzoylhypaconine (monoester-diterpenoid alkaloids, MDAs) and hypaconitine (diester-diterpenoid alkaloids) from processed aconite root, and metabolic trends of compounds from honey-processed liquorice and dried ginger were also performed. Results The absorption of MDAs from processed aconite root was increased by combination with honey-processed liquorice in ALD, but they were decreased significantly by the addition of dried ginger in SND. Take benzoylhypaconine for example, the P app, AP to BL soared from ( 3.13 ± 0.18) × 10 −7 cm/s in AD to (23.32 ± 3.51) × 10 −7 cm/s in ALD, while it dropped to (1.12 ± 0.17) × 10 −7 cm/s in SND. When herb combined decoctions metabolised by intestinal bacteria for 12 h, the efflux ratio of benzoylhypaconine were both increased from 0.56 to 1.21 in ALD and from 1.10 to 2.61 in SND, which was correlative with the generation of davidigenin and glycyrrhetic acid (the metabolites of chalcones and pentacyclic triterpenoids from liquorice) in ALD and with the metabolism of [6]-gingerol (the major compound from dried ginger) in SND, respectively. Conclusions Compatibility of SND altered the intestinal absorption of toxic MDAs and hypaconitine from processed aconite root. In SND, dried ginger rather than honey-processed liquorice played the role of detoxification of these toxic compounds in the intestinal absorption. The intestinal detoxification of SND was significantly and strongly correlative with metabolism of dried ginger and honey-processed liquorice by intestinal bacteria, simultaneously.
研究领域:
药理学
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民族药理学
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微生物学
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毒理学
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中医药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Jingjing Yao,Yajuan Guo,Ting Wan,Shaofang Yu,Qinghong Shen,Min Huang,Yu Li,Fuping Xu,Huiyan Zeng,Zhongqiu Liu,Linlin Lu
Ethnopharmacological relevance Aconitum carmichaelii Debx. exhibits overwhelming efficacy against heart failure, inflammation and pain, but its clinical application is limited by concomitant cardiotoxicity and neurotoxicity. Aconitine (AC), the most abundant bioactive alkaloid, has narrow therapeutic window, with well-defined toxic and therapeutic thresholds. However, the overlapping molecular targets mediating dual toxicity and efficacy of AC remain poorly characterized. Aims of the study This study aimed to evaluate dual pharmacological and toxicological roles of AC through integrative pharmacology and transgenic mouse models. Materials and methods The overlapping targets of AC-related toxicity/efficacy were identified based on integrative pharmacology. By generating Cyp3a −/− transgenic mice expressing human CYP3A4 (hCYP3A4), Ugt1, P-gp, Mrp2, BCRP, and Nrf2 knockout mice, the effects of AC on toxicity, pain, inflammation, and heart failure were assessed. Results We identified 143 overlapping targets predominantly enriched in metabolic pathways. Symptom-based toxicity scores were strikingly elevated in AC-exposed hCYP3A4, Mrp2 −/− , P-gp −/− , BCRP −/− , and Nrf2 −/− mice compared to WT mice. Additionally, AC prolonged the latency of response by approximately 18s, 15s, 14s, and 5s, respectively, in hCYP3A4, Mrp2 −/− , P-gp −/− , and Nrf2 −/− mice by hot plate assay. Interestingly, both toxicity score and analgesic latency initially increased and subsequently decreased, peaking at 60 min. AC obviously decreased the acetic acid-induced writhing and permeability by 45.7% and 22.2% in hCYP3A4 mice, whereas these changes were amplified in Mrp2 −/− mice compared to WT mice. Furthermore, AC attenuated DOX induced heart failure in hCYP3A4 mice, with an effective rate of 20.9%, with Septin4 implicated in AC-related metabolism. Conclusions Metabolic targets may elucidate the mechanistic overlap between the toxicity and efficacy of AC. Notably, hCYP3A4 exhibited heightened toxicity, alongside enhanced analgesic, anti-inflammatory, and cardioprotective effects. Our findings position metabolic pathways as critical nodes for AC-related dual effect, and establish Septin4 as a candidate mediator of its metabolic regulation.
研究领域:
药理学
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毒理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CURRENT DRUG METABOLISM
·
2024
·Vol. 25
·期 5
·317-329
·
IF 2.1
Xiaocui Li,Qi Liang,Caiyan Wang,Huawei Qiu,Tingting Lin,Wentao Li,Rong Zhang,Zhongqiu Liu,Lijun Zhu
BackgroundYunaconitine (YAC) is a hidden toxin that greatly threatens the life safety of patients who are prescribed herbal medicines containing Aconitum species; however, its underlying mechanism remains unclear.ObjectiveThe objective of this study is to elucidate the functions of P-glycoprotein (P-gp) in regulating the efficacy, toxicity, and pharmacokinetics of YAC.MethodsThe efflux function of P-gp on YAC was explored by using Caco-2 monolayers in combination with the P-gp inhibitor verapamil. The impact of P-gp on regulating the analgesic and anti-inflammatory effects, acute toxicity, tissue distribution, and pharmacokinetics of YAC was determined via male Mdr1a gene knocked-out mice and wild-type FVB mice.ResultsThe presence of verapamil significantly decreased the efflux ratio of YAC from 20.41 to 1.07 in Caco-2 monolayers (P < 0.05). Moreover, oral administration of 0.07 and 0.14 mg/kg YAC resulted in a notable decrease in writhing times in Mdr1a-/- mice by 23.53% and 49.27%, respectively, compared to wild-type FVB mice (P < 0.05). Additionally, the deficiency of P-gp remarkably decreased the half-lethal dose (LD50) of YAC from 2.13 to 0.24 mg/kg (P < 0.05). Moreover, the concentrations of YAC in the tissues of Mdr1a-/- mice were statistically higher than those in wild-type FVB mice (P < 0.05). Particularly, the brain accumulation of YAC in Mdr1a-/- mice significantly increased by 12- and 19-fold, respectively, after oral administration for 30 and 120 min, when compared to wild-type FVB mice (P < 0.05). There were no significant differences in the pharmacokinetic characteristics of YAC between Mdr1a-/- and wild-type FVB mice.ConclusionYAC is a sensitive substrate of P-gp. The absence of P-gp enhances the analgesic effect and toxicity of YAC by upregulating its brain accumulation. Co-administration with a P-gp inhibitor may lead to severe YAC poisoning.
研究领域:
药理学
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毒理学
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中药学
✓ 已验证
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Chen Ze-Yan,Wei Xu-Ya,Qiu Zi-Dong,Huang Yun,Tan Ting,Feng Yu-Lin,Guo Juan,Cui Guang-Hong,Huang Lu-Qi,Lai Chang-Jiang-Sheng
The herb-pair ginseng-Fuzi (the root of Aconitum carmichaelii) is the material basis of Shenfu prescriptions and is popular in traditional Chinese medicine for the treatment of heart failure, and even shock with severe-stage of COVID-19. A narrow therapeutic window of Fuzi may cause significant regional loss of property and life in clinics. Therefore, systemic elucidation of active components is crucial to improve the safety dose window of Shenfu oral prescriptions. A high performance liquid chromatography-mass spectrometry method was developed for quantification of 10 aconitines in SD rat plasma within 9 min. The limit of detection and the limit of quantification were below 0.032 ng/ml and 0.095 ng/ml, respectively. Furthermore, a systemic comparison with their pharmacokinetic characteristics after oral administration of a safe dosage of 2 g/kg of Fuzi and ginseng-Fuzi decoction for 24 h was conducted. Eight representative diester, monoester, and non-ester aconitines and two new active components (i.e., songorine and indaconitine) were all adopted to elucidating the differences of the pharmacokinetic parameters in vivo. The compatibility of Fuzi and ginseng could significantly increase the in vivo exposure of active components. The terminal elimination half-life and the area under the concentration-time curve of mesaconitine, benzoylaconitine, benzoylmesaconitine, benzoylhypaconitine, and songorine were all increased significantly. The hypaconitine, benzoylmesaconitine, and songorine were regarded as the main active components in vivo, which gave an effective clue for the development of new Shenfu oral prescriptions.
研究领域:
中药学
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药理学
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分析化学
✓ 已验证
DOI
高影响因子
JOURNAL OF FORENSIC SCIENCES
·
2021
·Vol. 66
·期 5
·2035-2040
·
IF 1.832
Yang Ya,Zhang Zhixiang,Liu Chao,Zhao Wei,Wang Zhiyong,Cheng Huafeng,Zhu Shaohua,Xu Hongfei
Aconitine is a natural toxic substance belonging to the family of aconitum alkaloids, which is used in small doses by Traditional Chinese practitioners. We present a case of accidental death due to acute aconitine poisoning. A 65-year-old Chinese man presented to a medical clinic with fever and shoulder pain. Soon after administration of intravenous ceftriaxone, a bottle of Chinese medicinal wine was administered. The man rapidly experienced headache, hearing loss and tinnitus, nausea, diarrhea, numbness of the lips, tongue, face, and the upper and lower extremities, cold sweat, fall of blood pressure, and discomfort of the entire body, and he died on the same day. Postmortem examination showed cyanosis of the nail beds, severe congestion in lungs and other organs, bilateral pleural effusions, and infiltration of basophils in the intestinal submucosa. No significant increase of IgE was found in the blood. Toxicological analysis detected aconitine in the medicinal wine, blood, and stomach contents by liquid chromatography–tandem mass spectrometry (LC-MS⁄MS). Aconitine was quantified in cardiac blood as 16.4 ng/ml, and in stomach contents (63.8 ng/ml) and wine sample (10.1 ug/ml). The cause of death was aconitine poisoning. This case report highlights the danger of aconitine. LC-MS⁄MS has the advantages of high analytic speed, sensitivity, and accuracy. It would be desirable for the government to control the use of aconitine-containing herbal extracts.
研究领域:
毒理学
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医学
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分析化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN CHINESE UNIVERSITIES
·
2014
·Vol. 30
·期 5
·731-737
·
IF 1.119
Ma Jingwei,Kan Hong,Ma Yinghui,Men Lihui,Pi Zifeng,Liu Zhiqiang,Liu Zhongying
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), aconitine( 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 Verapamil, 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 peiminine( 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.
研究领域:
药理学
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中药学
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生物化学
✓ 已验证
产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Mingmei Xiao,Jiuhua Zhang,Jiajin Wu,Ning Yuan,Tao Liu,Chunzhi Tang,Nenggui Xu,Qingxin Li,Jinchuan Wu,Shijie Li,Zhuoyue Song
3-Acetylaconitine (AAC) is a commercially analgesic drug for arthritis, however, due to its narrow safety range, its clinical application is limited. The objective of the study was to investigate the combined effect of Cucumaria frondosa polysaccharide (CFP) and AAC in microneedles on knee osteoarthritis (KOA). The characterization of microneedles was conducted and a rat model of monosodium iodoacetate (MIA)-induced KOA was established to evaluate the anti-inflammatory and analgesic activity in this study. The inhibitory effects on cartilage degradation and synovial inflammation were determined by morphological observation of the knee joint, pathological and imaging results. The von Frey pain threshold and hind limb weight bearing test were used to evaluate the effect of microneedles on pain relief. The results showed that microneedles had the mechanical strength to penetrate the skin and dissolved well in the skin for drug delivery within 30 min after patch administration. Furthermore, AAC-MN and CFP-AAC-MN both played roles in relieving pain, reducing cartilage degeneration and inhibiting synovial inflammation in KOA. In summary, CFP combined with AAC loading into microneedles exhibited higher skin penetration and more advantages in inhibiting cartilage damage and inflammation compared to AAC alone.
研究领域:
医学
·
药理学
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生物材料学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2019
·
IF 3.532
Chao Liu,Nabil Farah,Wei Weng,Baixin Jiao,Meiyue Shen,Liang Fang
Permeation enhancer strategy is used to develop Benzoylaconitine (BA) of high molecular weight (603.7 Da) into transdermal patch . The present study was to achieve a patch with good analgesic and anti-inflammatory effects and investigate the relationship between physicochemical parameters of enhancers and enhancement strength. In vitro skin permeation study was used to evaluate the effect of enhancers, and correlation study was conducted to clarify the relationship between physicochemical parameters of enhancer and permeation amount. The enhancement molecular mechanism was characterized using FT-IR and molecular modeling. Finally, pharmacodynamic effect of BA patch was evaluated with analgesic and anti-inflammatory assessment. The correlation analysis indicated that the optimized patch containing permeation enhancer Plurol® Oleique CC497 with high surface tension (43.0 dyne/m), demonstrated the strongest skin permeation amount of 5.50 ± 0.21 μg/cm 2 . According to the FT-IR and molecular modeling study, the enhancer with high surface tension demonstrated maximum interaction strength ( E mix = −9.20 kcal/mol) with skin lipid and affected the skin protein region, which strongly disturbed skin lipid arrangement according to the results of ATR-FTIR study (wavenumber variation of ν as CH2 of skin lipid > 2.00 cm −1 ) and molecular modeling (Cohesive Energy Density of skin lipid bilayer = 1.04E + 08 kcal/mol). It was indicated that only based on sufficient interaction strength and disturbing of both lipophilic and hydrophilic area of stratum corneum, permeation enhancer was able to demonstrated great permeation enhancement effect. Finally, BA transdermal patch was developed and showed excellent analgesic and anti-inflammatory effect, which was a potential preparation for the treatment of inflammatory pain .
研究领域:
药理学
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药物递送系统
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生物医学工程
✓ 已验证
DOI
高影响因子
Communications Biology
·
2019
·Vol. 2
·期 1
·1-11
·
IF 0
Lin Yanke,Wang Shuai,Zhou Ziyue,Guo Lianxia,Yu Fangjun,Wu Baojian
Metabolism is a major defense mechanism of the body against xenobiotic threats. Here we unravel a critical role of Bmal1 for circadian clock-controlled Cyp3a11 expression and xenobiotic metabolism. Bmal1 deficiency decreases the mRNA, protein and microsomal activity of Cyp3a11, and blunts their circadian rhythms in mice. A screen for Cyp3a11 regulators identifies two circadian genes Dbp and Hnf4α as potential regulatory mediators. Cell-based experiments confirm that Dbp and Hnf4α activate Cyp3a11 transcription by their binding to a D-box and a DR1 element in the Cyp3a11 promoter, respectively. Bmal1 binds to the P1 distal promoter to regulate Hnf4α transcriptionally. Cellular regulation of Cyp3a11 by Bmal1 is Dbp- and Hnf4α-dependent. Bmal1 deficiency sensitizes mice to toxicities of drugs such as aconitine and triptolide (and blunts circadian toxicity rhythmicities) due to elevated drug exposure. In summary, Bmal1 connects circadian clock and Cyp3a11 metabolism, thereby impacting drug detoxification as a function of daily time.
研究领域:
药理学
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分子生物学
·
时间生物学
✓ 已验证
产品关联
DOI
PubMed
SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
·
2020
·
IF 3.232
Kang Luo,Haicheng Chen,Qing Zhou,Zhihong Yan,Zhengquan Su,Kang Li
Iron disulfide (FeS 2 ) quantum dots have potential applications in various fields such as photocatalysis , lithium-ion batteries and bioimaging. At present, there is no report on the fluorescent characteristics of FeS 2 quantum dots (FeS 2 QDs). In this work, a synthesis of multiple-color emission FeS 2 QDs by changing the temperature, time and raw ratio has been reported. The blue, green, yellow and red emission FeS 2 QDs can be obtained, respectively. They were characterized by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS) and transmission electron microscope (TEM). On this basis, a novel molecular imprinting ratiometric fluorescence sensor (MIR sensor) had been constructed, in which the blue-emission FeS 2 QDs (b-FeS 2 QDs) was used as a fluorescent responsive signal material and the yellow-emission FeS 2 QDs (y-FeS 2 QDs) was served as a reference signal material. And this MIR sensor was applied for highly selective and sensitive detection of ACO in traditional Chinese medicine (TCM). Under the optimum conditions, the MIR sensor exhibited an excellent linear relationship between the fluorescence intensity ratio (I 443 /I 590 ) and the concentration of ACO in the range of 0.05–5.0 μM with a detection limit of 24 nM. Furthermore, the established method was successfully utilized to the detection of ACO in TCM Fuzi Lizhong Pills with satisfactory results. It provided a reference for the application of the FeS 2 QDs with multiple color emission and the detection of the hazardous alkaloids.
研究领域:
材料科学
·
分析化学
·
生物医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）