Evodiamine: A Extremely Potential Drug Development Candidate of Alkaloids from Evodia rutaecarpa.

Evodiamine (EVO) is a tryptamine indole alkaloid and the main active ingredient in Evodia rutaecarpa. In recent years, the antitumor, cardioprotective, anti-inflammatory, and anti-Alzheimer's disease effects of EVO have been reported. EVO exerts antitumor effects by inhibiting tumor cell activity and proliferation, blocking the cell cycle, promoting apoptosis and autophagy, and inhibiting the formation of the tumor microvasculature. However, EVO has poor solubility and low bioavailability. Several derivatives with high antitumor activity have been discovered through the structural optimization of EVO, and new drug delivery systems have been developed to improve the solubility and bioavailability of EVO. Current research found that EVO could have toxic effects, such as hepatotoxicity, nephrotoxicity, and cardiac toxicity. This article reviews the pharmacological activity, derivatives, drug delivery systems, toxicity, and pharmacokinetics of EVO and provides research ideas and references for its further in-depth development and clinical applications.

Development of an integrated strategy for comprehensive characterization of Sinomenii Caulis extract and metabolites in rats based on UPLC/Q-TOF-MS.

Sinomenii Caulis (SC), a commonly used traditional Chinese medicine for its therapeutic effects on rheumatoid arthritis, contains rich chemical components. At present, most studies mainly focus on sinomenine, with little research on other alkaloids. In this study, a comprehensive profile of compounds in SC extract, and biological samples of rats (including bile, urine, feces, and plasma) after oral administration of SC extract was conducted via ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS). The fragmentation patterns and potential biotransformation pathways of six main types of alkaloids in SC were summarized, and the corresponding characteristic product ions, relative ion intensity, and neutral losses were obtained to achieve rapid classification and identification of complex components of SC from in vitro to in vivo. As a result, a total of 114 alkaloid compounds were identified, including 12 benzyl alkaloids, 4 isoquinolone alkaloids, 32 aporphine alkaloids, 28 protoberberine alkaloids, 34 morphinan alkaloids and 4 organic amine alkaloids. After administration of SC extract to rats, a total of 324 prototypes and metabolites were identified from rat plasma, urine, feces and bile, including 81 aporphines, 95 protoberberines, 117 morphinans and 31 benzylisoquinolines. The main types of metabolites were demethylation, hydrogenation, dehydrogenation, aldehydation, oxidation, methylation, sulfate esterification, glucuronidation, glucose conjugation, glycine conjugation, acetylation, and dihydroxylation. In summary, this integrated strategy provides an additional approach for the incomplete identification caused by compound diversity and low abundance, laying the foundation for the discovery of new bioactive compounds of SC against rheumatoid arthritis.

The synthetic cathinones MDPHP and MDPV: Comparison of the acute effects in mice, in silico ADMET profiles and clinical reports.

The 3,4-methylenedioxy-alpha-pyrrolidinohexanophenone (MDPHP) is a synthetic cathinone closely related to 3,4-methylenedioxypyrovalerone (MDPV), one of the most common synthetic cathinones present in the "bath salts". MDPHP has recently gained attention due to increasing seizures and involvement in human intoxications which occurred in Europe and Italy in the last years, but currently there is a lack of information about its pharmaco-toxicological effects. With the aim at filling this gap, the present study is endeavoured to (i) evaluate the effects of acute administration of MDPHP (0.01-20 mg/kg; i.p.) on behaviour, cardiorespiratory and cardiovascular parameters in CD-1 male mice, comparing them to those observed after administration of MDPV; (ii) predict the ADMET profile of the two analogues using the Plus ADMET Predictor®; (iii) present clinical data related to MDPHP and MDPV-induced intoxications recorded between 2011 and 2023 by the Pavia Poison Control Centre (PCC) - National Toxicology Information Centre (Istituti Clinici Scientifici Maugeri, IRCCS Pavia, Italy). Our results substantiated that MDPHP and MDPV similarly affect sensorimotor and behavioural responses in mice, importantly increased locomotion and induced aggressive behaviour, and, at higher dosage, increased heart rate and blood pressure. These findings are in line with those observed in humans, revealing severe toxidromes typically characterized by Central Nervous System (CNS) alterations (behavioural/neuropsychiatric symptoms), including psychomotor agitation and aggressiveness, cardiovascular and respiratory disorders (e.g. tachycardia, hypertension, dyspnoea), and other peripheral symptoms (e.g. hyperthermia, acidosis, rhabdomyolysis).

Characterization of active alkaloids and metabolites in rats after oral administration of Zuojin Pill using UHPLC-Q-TOF-MS combined with bioinformatics and molecular docking analyses.

Zuojin Pill (ZJP), a traditional Chinese medicine prescription composed of Rhizoma Coptidis and Euodiae Fructus in the ratio of 6:1 (w/w), has been widely used for the treatment of gastric disorders. However, an in-depth understanding of in vivo metabolism and distribution profiles of protoberberine alkaloids (PBAs) and indole alkaloids (IDAs) in ZJP is lacking. In this study, a method using ultra-high performance liquid chromatography coupled with quadruple time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was developed to systematically screen the alkaloids and their metabolites in rat plasma and various tissues after oral administration of ZJP. Furthermore, bioinformatics and molecular docking analyses were conducted to elucidate the contribution of the alkaloids and metabolites enriched in the stomach to the therapeutic effect of ZJP on gastritis. A total of 33 compounds, including 7 prototype alkaloids and 26 metabolites, were chemically defined or tentatively identified in this work. The metabolic pathways of PBAs (hydroxylation, oxidation, reduction, demethylation, demethylenation, glucuronide conjugation, sulfate conjugation) and IDAs (hydroxylation, glucuronide conjugation) were revealed. Notably, 7 prototype alkaloids and 18 metabolites were detected in the stomach, indicating their propensity for gastric distribution. These alkaloids and metabolites showed strong affinities with the 7 hub targets associated with gastritis, such as CCR7, CXCR4, IL6, IFNG, CCL2, TNF, and PTPRC, and could be considered the potential active substances of ZJP for treating gastritis. In conclusion, this study clarified the gastric distribution propensity of PBAs and IDAs and their metabolites, as well as their favorable binding interactions with gastritis-related targets, which could provide essential data for the further study of the pharmacodynamic material basis and gastroprotective mechanism of ZJP.

Characterization of the Components and Metabolites of Achyranthes Bidentata in the Plasma and Brain Tissue of Rats Based on Ultrahigh Performance Liquid Chromatography-High-Resolution Mass Spectrometry (UHPLC-HR-MS).

BACKGROUND: Achyranthes bidentata (AR) is a traditional Chinese herb used for the treatment of hypertension and cerebral ischemia, but its pharmacological effects are not known. AIM OF STUDY: We aimed to detect and accurately identify the components and metabolites of AR in the plasma and brain tissue of Sprague Dawley rats. METHODS: We employed ultrahigh performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HR-MS) to detect AR components in the plasma and brain tissue of rats. The absorption and metabolites in the plasma and brain tissue of normal control rats and rats that underwent middle cerebral artery occlusion (MCAO) were characterized and compared. RESULTS: A total of 281 compounds, including alkaloids, flavonoids, terpenoids, phenylpropanes, sugars and glycosides, steroids, triterpenes, amino acids, and peptides, was identified in samples of Achyranthes bidentata (TCM-AR). Four types of absorbable prototype components and 48 kinds of metabolites were identified in rats in the normal control plasma group which were given AR (AR plasma group), and five kinds of metabolites were identified in rats of the normal control brain tissue group which were given AR (AR brain group). Three absorbed prototype components and 13 metabolites were identified in the plasma of rats which underwent MCAO and were given AR (MCAO + AR plasma group). Six absorbed prototype components and two metabolites were identified in the brain tissue of rats who underwent MCAO and were administered AR (MCAO + AR brain group). These results showed that, after the oral administration of AR, the number of identified components in plasma was more than that in brain tissue. The number of prototype components in the AR plasma group was higher than that in the MCAO + AR plasma group, which may indicate that metabolite absorption in rats undergoing MCAO was worse. The number of prototype components in the MCAO + AR brain group was higher than that in the AR brain group, indicating that the blood-brain barrier was destroyed after MCAO, resulting in more compounds entering brain tissue. CONCLUSIONS: UHPLC-HR-MS was used to rapidly analyze the components and metabolites of AR in the blood and brain of rats under normal and pathologic conditions, and to comprehensively characterize the components of TCM-AR. We also analyzed and compared the absorbable components and metabolites of normal rats under cerebral ischemia-reperfusion injury to explore the potential mechanism of action. This method could be applied to various Chinese herbs and disease models, which could promote TCM modernization.

Disposition Kinetics of Cathinone and its Metabolites after Oral Administration in Rats.

BACKGROUND: Cathinone is a natural stimulant found in the Catha edulis plant. Its derivatives make up the largest group of new psychoactive substances. In order to better understand its effects, it is imperative to investigate its distribution, pharmacokinetics, and metabolic profile. However, the existing literature on cathinone remains limited. OBJECTIVE: This study aimed to investigate the disposition kinetics and metabolic profile of cathinone and its metabolite cathine through a single oral dose of cathinone administration in rats. METHODS: Cathinone and cathine concentrations were identified and quantified using ion trap liquid chromatography- mass spectrometry (LC-IT/MS). The metabolic profile in the serum, brain, lung, liver, kidney, and heart was analyzed at specific time points (0, 0.5, 2.5, 6, 12, 24, 48, and 72 hours) using the ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) method. RESULTS: The highest concentration of cathinone was found in the kidney (1438.6 µg/L, which gradually decreased to 1.97 within 48 h and disappeared after 72 h. Cathinone levels in the lungs, liver, and heart were 859, 798.9, and 385.8 µg/L, respectively, within half an hour. However, within 2.5 hours, these levels decreased to 608.1, 429.3, and 309.1 µg/L and became undetectable after 24 h. In the rat brain, cathinone levels dropped quickly and were undetectable within six hours, decreasing from 712.7 µg/L after 30 min. In the brain and serum, cathine reached its highest levels at 2.5 hours, while in other organs, it peaked at 0.5 hours, indicating slower conversion of cathinone to cathine in the brain and serum. CONCLUSION: This study revealed a dynamic interplay between cathinone disposition kinetics and its impact on organ-specific metabolic profiles in rats. These results have significant implications for drug development, pharmacovigilance, and clinical practices involving cathinone. Investigating the correlation between the changes in biomarkers found in the brain and the levels of cathinone and cathine is essential for informed decision- making in medical practices and further research into the pharmacological properties of cathinone.

Comprehensive Analysis of Chemical Ingredients of Waiganfengsha Granule and Absorbed Components in Rat Plasma Based on UHPLC-Q-TOF-MS.

OBJECTIVE: Waiganfengsha Granule, an over-the-counter drug, is commonly used for treating windheat cold and sore throat in clinical settings. However, its material basis of medicinal efficacy is still unclear. In this study, an efficient integrated analytical strategy was established for its chemical and metabolite profiles study. METHODS: Firstly, to avoid the possible false-positive results of structural elucidation, an in-house component library that contains chemical constituents reported in the literature from the six individual medicines of Waiganfengsha Granule was established. Secondary, mass data post-processing techniques, including precursor ion list and neutral loss filtering, were applied to enhance the identification accuracy. Thirdly, for the rapid characterization of those absorbed components after oral administration in rats, the identified chemical constituents were used as candidate components for the serum analysis. By comparing the retention time and analyzing mass data, the metabolites in rat plasma were identified. RESULTS: As a result, 57 chemical ingredients were identified, including 21 phenolic acids, 9 alkaloids, 2 flavonoids, 5 lignins, 13 saponins, and 7 other compounds. Among these, 12 compounds were unambiguously identified by comparison with reference standards, and 45 were tentatively characterized by analyzing their accurate MS data, MS/MS fragmentation patterns, and also by comparison with those data reported in the literature. Additionally, 46 metabolites were detected and identified in rat plasma. CONCLUSION: This study is beneficial for understanding the chemical composition and metabolic profiles of Waiganfengsha Granule, and the results obtained might provide a solid basis for further studies on its functional mechanism.

Multicomponent qualitative and quantitative analysis of Farfarae Flos in serum using UHPLC-Q TOF-MS.

Farfarae Flos is a traditional herb widely employed for treating coughs, bronchitis, and asthmatic disorders. In the current study, we utilized SWATH and IDA data acquisition modes in combination with multiple data processing techniques to identify Farfarae Flos metabolites in mice serum. A total of 56 compounds were characterized, including 31 phenolic acids, 13 flavonoids, 11 sesquiterpenoids and 1 alkaloid. Further quantitative analysis was conducted on 12 absorbed metabolites, utilizing a newly developed and rigorously validated analytical method. Our approach demonstrated an acceptable level of specificity, accuracy, precision, and stability. When applied to compare the serum of mice treated with FF, all 12 metabolites showed the highest concentration at 0.5 h. Overall, this study presented a novel strategy for unraveling the active compounds of FF via serum pharmacochemistry analysis, which made a foundation for exploring the pharmacodynamic material basis of FF.

Comparative Pharmacokinetics of Curcuminoids from Water-Dispersible Turmeric Extract Against a Curcuminoids-Piperine Combination: An Open-Label, Randomized, Balanced, 2-Treatment, 2-Sequence, 2-Period Crossover Study.

Objective: Curcuminoids, the major component of which is curcumin, are natural polyphenolic compounds from the rhizome of Curcuma longa Linn. and possess extensive biopharmacological properties that are limited in humans due to poor bioavailability. Currently, most commercial bioavailable turmeric extracts use synthetic excipients or the addition of piperine to enhance bioavailability, and are needed in multiple daily doses to achieve clinical efficacy. This study was conducted to compare the bioavailability of a natural, water-dispersible turmeric extract containing 60% natural curcuminoids, the test product, WDTE60N (1 × 250 mg per day), with the reference product, turmeric extract capsules (500 mg curcuminoids and 5 mg piperine, CPC; 3 × 500 mg per day). Methods: Sixteen healthy adult male subjects fasted overnight for 10 hours and then were dosed with either one capsule of the test product WDTE60N or three capsules of reference product CPC orally (One capsule administered at every 6 hours interval i.e. at 0.00 hrs, 6.00 hrs and at 12.00 hrs) in each study period. Blood sampling before and after dosing was carried out at defined time points at -12.00, -02.00, 00.00 (within 10 minutes prior to dosing) hours in morning before dosing and post-dose (First dose) at 00.50, 01.00, 02.00, 03.00, 04.00, 05.00, 06.50, 07.00, 08.00, 09.00, 10.00, 11.00, 12.50, 13.00, 14.00, 16.00, 18.00, 20.00 and 24.00 hours in each period. Plasma concentration of curcuminoids was determined using a validated liquid chromatography with tandem mass spectrometry bioanalytical method. Results: The Cmax (GLSM) for the test product WDTE60N was observed to be 74.56 ng/mL; and same for the reference CPC was 22.75 ng/mL. AUC0-t (GLSM) for test WDTE60N was 419.00 h∙ng/mL; and for reference CPC it was 359.86 h∙ng/mL for total curcuminoids. Conclusion: The test formulation WDTE60N showed improved relative absorption and equivalent exposure at a 10-fold-lower dose of actives than the reference formulation CPC.

Formation of multiple ion types during MALDI imaging mass spectrometry analysis of Mitragyna speciosa alkaloids in dosed rat brain tissue.

Mitragyna speciosa, more commonly known as kratom, has emerged as an alternative to treat chronic pain and addiction. However, the alkaloid components of kratom, which are the major contributors to kratom's pharmaceutical properties, have not yet been fully investigated. In this study, matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry was used to map the biodistribution of three alkaloids (corynantheidine, mitragynine, and speciogynine) in rat brain tissues. The alkaloids produced three main ion types during MALDI analysis: [M + H]+, [M - H]+, and [M - 3H]+. Contrary to previous reports suggesting that the [M - H]+ and [M - 3H]+ ion types form during laser ablation, these ion types can also be produced during the MALDI matrix application process. Several strategies are proposed to accurately map the biodistribution of the alkaloids. Due to differences in the relative abundances of the ions in different biological regions of the tissue, differences in ionization efficiencies of the ions, and potential overlap of the [M - H]+ and [M - 3H]+ ion types with endogenous metabolites of the same empirical formula, a matrix that mainly produces the [M + H]+ ion type is optimal for accurate mapping of the alkaloids. Alternatively, the most abundant ion type can be mapped or the intensities of all ion types can be summed together to generate a composite image. The accuracy of each of these approaches is explored and validated.

Determination of alkaloid-inspired molecule vindeburnol in rabbit plasma by UPLC-HRMS and its application to pharmacokinetic studies and preliminary metabolite identification.

The eburnamine-vincamine alkaloids exhibit a range of pharmacological activities. There is a limited understanding of the pharmacokinetics and pharmacodynamics of vindeburnol, a synthetic derivative of this chemical class of alkaloids. A fast and reliable UPLC-HRMS method was developed and validated to quantify vindeburnol in Soviet Chinchilla rabbit plasma from pharmacokinetics studies. An ultra-performance liquid chromatography system equipped with a Waters Acquity UPLC HSS T3 column was used for chromatographic separation by gradient elution with 0.1% (v/v) formic acid in water and acetonitrile. An Impact II QqTOF high-resolution mass spectrometer equipped with an Apollo II electrospray ionization source was used for analysis in positive mode; the ions [M+H]+m/z 269.1648 ± 0.003 and m/z 351.2067 ± 0.003 were monitored for vindeburnol and internal standard (vinpocetine), respectively. Preliminary metabolite profiling was also performed, and the pharmacokinetics of the identified metabolites were evaluated. The mean retention times for vindeburnol and vinpocetine were 2.0 and 3.5 min. The UPLC-HRMS method was validated with accuracy and precision within the 15% acceptance limit (8.2% and 11.0%, respectively). The mean extraction recovery value of vindeburnol from rabbit plasma was 77%. Pharmacokinetic evaluation of vindeburnol revealed that the compound is distributed rapidly with a short elimination half-life. Vindeburnol undergoes extensive first-pass metabolism and is metabolized into hydroxyvindeburnol and vindeburnol glucuronide.

[Pharmacokinetics and tissue distribution of four alkaloids in Ermiao Pills and Sanmiao Pills in normal and arthritic model rats].

This work aimed to investigate the differences of pharmacokinetics and tissue distribution of four alkaloids in Ermiao Pills and Sanmiao Pills in normal and arthritic model rats. The rat model of arthritis was established by injecting Freund's complete adjuvant, and ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) in the positive ion multiple reaction monitoring(MRM) mode was used for the determination of four alkaloids in plasma and tissues of normal and arthritic rats after administration of Ermiao Pills and Sanmiao Pills, respectively. The differences in pharmacokinetics and tissue distribution of the four active components were compared, and the effect of Achyranthis Bidentatae Radix on the major components of Sanmiao Pills was explored. This study established an UPLC-MS/MS for simultaneous determination of four alkaloids, and the specificity, linearity, accuracy, precision, and stability of this method all met the requirements. Pharmacokinetics study found that as compared with normal rats, the AUC and C_(max) of phellodendrine, magnoflorine, berberine and palmatine in model rats were significantly decreased after administration of Ermiao Pills, the clearance rate CL/F was significantly increased, and the distribution and tissue/plasma concentration ratio of the four alkaloids in the liver, kidney, and joint were significantly reduced. Achyranthis Bidentatae Radix increased the AUC of phellodendrine, berberine, and palmatine, reduced the clearance rate, and significantly increased the distribution of the four alkaloids in the liver, kidney, and joints in arthritic rats. However, it had no significant effect on the pharmacokinetics and tissue distribution of the four alkaloids in normal rats. These results suggest that Achyranthis Bidentatae Radix may play a guiding role in meridian through increasing the tissue distribution of effective components in Sanmiao Pills under arthritis states.

Complexation of Apigenin and Oxymatrine Leading to Enhanced Anti-inflammatory Activity.

Apigenin (APG) is a well-known dietary flavonoid with multiple bioactivities, but its poor aqueous solubility may result in low oral bioavailability and thus compromised therapeutic effects. In the present study, APG was complexed with oxymatrine (OMT), a natural quinolizidine alkaloid, for enhanced anti-inflammatory activity, and the related mechanisms in the interaction of APG with OMT were investigated. Fourier transform-infrared spectroscopy, fluorescence spectroscopy, Raman spectroscopy, and proton nuclear magnetic resonance spectroscopy characterizations demonstrated the occurrence of an APG-OMT complex formed at a molar ratio of 1:2. Then, molecular dynamics simulations and quantum chemical calculations were utilized to elucidate that hydrogen bonding, van der Waals forces, and hydrophobic effects were the main forces acting in the formation of the APG-OMT complex. Pharmacokinetic studies in rats demonstrated that the oral bioavailability of APG in the APG-OMT complex was significantly higher than that of APG alone. Finally, bioactivity evaluation in the lipopolysaccharide-induced acute inflammatory injury mouse models showed that the APG-OMT complex exhibited more potent anti-inflammatory effects than APG alone. This study confirmed that APG and OMT exerted enhanced anti-inflammatory effects through self-complexation, which may provide a novel strategy for improving the bioavailability and bioactivity of natural product mixtures.

HPLC-MS/MS analysis of primary alkaloids in rat plasma after oral administration of "Nux vomica - Glycyrrhiza glabra decoction": A pharmacokinetic study.

ETHNOPHARMACOLOGICAL RELEVANCE: Decoction is the most common form of administering traditional Chinese medicine (TCM). During the preparation of decoction, the high temperature and complex chemical environment result in the formation of complex and multiple phases. The differences in drug components in different phases induce gastrointestinal absorption and physiological response. Nux vomica (Strychnos nux-vomica L) is a typical toxic TCM used in China, with remarkable pharmacological activity. In order to reduce its toxicity, nux vomica (NV) is often decocted with Glycyrrhiza glabra (GG) in clinic, and the detoxification mechanism has always been the focus of research interest. Most studies investigated the compatibility of NV-GG, but the in vivo behavior of individual constituents based on phase state has yet to be elucidated. AIM OF THE STUDY: To investigate the pharmacokinetic behavior of typical toxic components in different phase states of "NV-GG decoction" in rat plasma. MATERIALS AND METHODS: The sediment, suspension, colloid and true solution of "NV-GG decoction" was obtained via physical methods. The main components in different phase states were analyzed via reliable UFLC-Q-TOF-MS high-resolution mass spectrometry. A rapid and accurate HPLC-qqq-MS/MS method was established and validated for accurate determination of brucine and strychnine levels in plasma, followed by pharmacokinetic evaluation of different phase states of "NV-GG decoction" in rats. Kinetex F5 100A (50 mm × 3.0 mm, 2.6 µm) column was used for chromatographic separation. Aqueous solution containing acetonitrile and 0.1% formic acid was used as the mobile phase, followed by gradient elution at 0.4 mL/min. Mass spectra were detected by electrospray ionization (ESI) multiple reaction monitoring (MRM) in positive ion mode. RESULTS: Fifteen different alkaloids were detected in different phase states of "NV-GG decoction". Strychnine and brucine, which are toxic components with high content, were selected for quantitative analysis. The established UPLC-qqq-MS/MS method is accurate and reliable with a good linearity (R2 > 0.99) in the respective concentration range, satisfying the quantitative requirements. The pharmacokinetic parameters of different phase states of rats differed significantly after gavage. The deposition phase was the most prominent. The index components showed higher Cmax, AUC0 and Tmax, while the T1/2, MRT, V/F and CL/F were the smallest, with a relatively slow plasma clearance rate in rats. The true solution group showed the lowest Tmax and the fastest absorption. CONCLUSION: This method has been successfully utilized to study the pharmacokinetics of different phase states of "NV-GG decoction". Among the four phases, the deposition phase contributed to a large proportion of the in vivo kinetic behavior similar to that of sustained-release preparations, with slow absorption of toxic components and prolonged peak time. The pharmacokinetic parameters and plasma concentration-time curves of each phase can be used to study toxicity reduction of NV-GG and increase its biocompatibility.

Mesembryanthemum tortuosum L. alkaloids modify anxiety-like behaviour in a zebrafish model.

ETHNOPHARMACOLOGICAL RELEVANCE: Mesembryanthemum tortuosum L. (previously known as Sceletium tortuosum (L.) N.E. Br.) is indigenous to South Africa and traditionally used to alleviate anxiety, stress and depression. Mesembrine and its alkaloid analogues such as mesembrenone, mesembrenol and mesembranol have been identified as the key compounds responsible for the reported effects on the central nervous system. AIM OF THE STUDY: To investigate M. tortuosum alkaloids for possible anxiolytic-like effects in the 5-dpf in vivo zebrafish model by assessing thigmotaxis and locomotor activity. MATERIALS AND METHODS: Locomotor activity and reverse-thigmotaxis, recognised anxiety-related behaviours in 5-days post fertilization zebrafish larvae, were analysed under simulated stressful conditions of alternating light-dark challenges. Cheminformatics screening and molecular docking were also performed to rationalize the inhibitory activity of the alkaloids on the serotonin reuptake transporter, the accepted primary mechanism of action of selective serotonin reuptake inhibitors. Mesembrine has been reported to have inhibitory effects on serotonin reuptake, with consequential anti-depressant and anxiolytic effects. RESULTS: All four alkaloids assessed decreased the anxiety-related behaviour of zebrafish larvae exposed to the light-dark challenge. Significant increases in the percentage of time spent in the central arena during the dark phase were also observed when larvae were exposed to the pure alkaloids (mesembrenone, mesembrenol, mesembrine and mesembrenol) compared to the control. However, mesembrenone and mesembranol demonstrated a greater anxiolytic-like effect than the other alkaloids. In addition to favourable pharmacokinetic and physicochemical properties revealed via in silico predictions, high-affinity interactions characterized the binding of the alkaloids with the serotonin transporter. CONCLUSIONS: M. tortuosum alkaloids demonstrated an anxiolytic-like effect in zebrafish larvae providing evidence for its traditional and modern day use as an anxiolytic.

Simultaneous determination of 11 alkaloids in rat plasma by LC-ESI-MS/MS and a pharmacokinetic study after oral administration of total alkaloids extracted from Naucleaofficinalis.

ETHNOPHARMACOLOGICAL RELEVANCE: Nauclea officinalis, a widely used Li medicine, has been used for the treatment of cold, fever, bronchitis, pneumonia, acute tonsillitis, and other ailments. Modern pharmacological studies have demonstrated that the most abundant and active components in N. officinalis are alkaloids, which possess various biological properties such as antibacterial and antitumor activities. AIM OF THE STUDY: To investigate the phytochemical profile of a selected group of alkaloids from the N. officinalis total alkaloids, and to determine the chemical profile of the alkaloids extracted from rat plasma. Further investigation was conducted to determine the pharmacokinetic behaviors of 11 selected major alkaloids, including pumiloside, naucleoxoside A, naucleoxoside B, nauclefine, angustidine, angustoline, (3S,19S)-3,14-dihydroangustoline,[α]D20: (-)191°, (3S,19R)-3,14-dihydroangustoline, [α]D20: (-) 294.7°, strictosamide, angustine, and 3,14-dihydroangustine. MATERIALS AND METHODS: N. officinalis total alkaloids were extracted with 79% ethanol and enriched with AB-8 macroporous resin. The phytochemical profile of alkaloids from the N. officinalis total alkaloids and the chemical profile of the alkaloids extracted from rat plasma were first analyzed by UPLC-Q-TOF-MS/MS. A simple, convenient, and sensitive LC-ESI-MS/MS method was subsequently developed and validated for the simultaneous determination of major active alkaloids in rat plasma after oral administration of N. officinalis total alkaloids. After addition of an internal standard (verapamil), plasma samples were pretreated first by protein precipitation with methanol and then underwent liquid-liquid extraction with ethyl acetate. Chromatographic separation was achieved using a Waters BEH C18 column (2.1 mm × 100 mm, 1.7 µm) at 30 °C, with gradient elution using a mobile phase consisting of 0.1% formic acid aqueous solution (A) and acetonitrile (B), a flow rate of 0.2 mL/min, and a total run time of 30 min. The detection was performed using an electrospray ionization triple quadrupole tandem mass spectrometer with multiple reaction monitoring and positive ionization mode. RESULTS: Based on the fragmentation patterns of 11 authentic alkaloids and previous reports, 55 alkaloids were identified or tentatively identified in the N. officinalis total alkaloids. Among them, 25 alkaloids were absorbed through the gastrointestinal tract in rats after administration of the N. officinalis total alkaloids. The 11 alkaloids were selected for quantitative analysis. The established quantitative method was fully validated and proved to be sensitive and specific. Satisfactory linearity of the 11 alkaloids obtained in the respective concentration ranges (r > 0.9931). The lower limits of quantification for strictosamide was 20.86 ng/ml, and the other ten alkaloids were all less than 4.47 ng/ml in rat plasma. The intra-and inter-day precision was less than 15% for all 11 alkaloids in terms of relative standard deviation, and the accuracies ranged from -11.4% to 11.1% in terms of relative error. Extraction recovery, matrix effect, and stability were within the required limits in rat plasma. CONCLUSION: The validated method was successfully applied to investigate the pharmacokinetics of the 11 alkaloids in rat plasma after oral administration of N. officinalis total alkaloids. Eleven alkaloids were rapidly absorbed to achieve a maximum plasma concentration with Tmax from 0.25 h to 1.5 h after oral administration. The pharmacokinetic parameters and plasma concentration-time profiles will prove valuable in pre-clinical and clinical investigations on the disposition of N. officinalis total alkaloids.

Comparative pharmacokinetics, intestinal absorption and urinary excretion of six alkaloids from herb pair Phellodendri Chinensis cortex-Atractylodis Rhizoma.

Phellodendri Chinensis Cortex (PCC) and Atractylodis Rhizoma (AR) are frequently used as herb pair to treat eczema and gout owing to their synergistic effects. Alkaloids are the major ingredients from PCC and the effect of their combination on the in vivo processing of alkaloids remains unclear. In this study, a simple and reliable UPLC-MS/MS method for simultaneous determination of six alkaloids in rat plasma was developed. This method was applied to a comparative pharmacokinetic study between PCC and PCC-AR in rats. Effect of AR on absorption of alkaloids was investigated by a single-pass intestinal perfusion study. The effect of AR on urinary excretion of alkaloids was studied. Pharmacokinetic studies showed that the values of rea under the concentration-time curve of phellodendrine, magnoflorine and palmatine were greater in the PCC-AR group than in the PCC group. The intestinal absorptive parameters absorption rate constant and effective permeability of phellodendrine and jatrorrhizine in PCC-AR groups were higher than those in the PCC group. Urinary excretion studies revealed that the excreted amount of alkaloids in the PCC-AR group was lower than that in the PCC group. The results revealed that the combination of PCC and AR improves intestinal absorption of alkaloids and reduces their urinary excretion, which enhances their systemic exposure. This study may explain the synergetic effects of PCC and AR in clinical applications.

A novel UPLC-MS/MS method for simultaneous quantification of trigonelline, 4-hydroxyisoleucine, and diosgenin from Trigonella foenum-graecum extract: Application to pharmacokinetic study in healthy and type 2 diabetic rats.

Trigonelline (TR), 4-hydroxyisoleucine (4-HI), and diosgenin (DG) are the main bioactives of the purified standardized extract of the popular plant Trigonella foenum-graecum L. (TFG), and it has been proven effective for the treatment of various diseases. However, to the best of our knowledge, no study has investigated the pharmacokinetic parameters of purified standardized T. foenum-graecum extract in normal and diabetic Wistar rats. The present study has developed and validated a rapid, reliable, and sensitive simultaneous ultra-performance liquid chromatography MS method to estimate these bioactives. The chromatographic separation was achieved using methanol, acetonitrile, and 0.1% formic acid with the ideal gradient flow system on a BEH Shield RP 18 column. A positive electrospray ionization mode was selected to estimate m/z values of TR (138.14 > 94.63), 4-HI (148.19 > 74.08), and DG (415.54 > 271.33). The method was robust and reproducible over the linearity range of 60-5000, 6-5000, and 15-5000 ng/mL for TR, 4-HI, and DG, respectively. Using this novel validated method, we investigated the pharmacokinetic parameters of bioactives using Phoenix WinNonlin version 8.0 (Certera) in normal and diabetic rats. The assay was successfully applied for the estimation of pharmacokinetic parameters using noncompartmental analysis. This investigation shows that the absorption rate increased, whereas distribution and elimination processes slowed down in diabetic rats compared with normal rats.

Preparation of magnetic yolk-shell structured metal-organic framework material and its application in pharmacokinetics study of alkaloids.

In this study, a magnetic yolk-shell structured metal-organic framework material (Fe3O4@YS-UiO-66-NH2) is prepared by the directional etching of Co2+/peroxymonosulfate and in situ magnetization. The characteristic properties of the material were investigated by using field emission scanning electron microscopy, transmission electron microscopy, energy-dispersive X-ray spectroscopy, X-ray powder diffraction, Fourier transform infrared spectroscopy, vibrating sample magnetometer, Brunauer-Emmett-Teller, and contact angle test. The Fe3O4@YS-UiO-66-NH2 shows the advantages of large surface area, good magnetic property, and satisfactory stability, as well as giving high affinity to alkaloids (ALs) via hydrophilic interaction, hydrogen bonding, and π-π interaction. The results of static adsorption experiment indicate that the Fe3O4@YS-UiO-66-NH2 possesses high adsorption capacity towards ALs and the adsorption behaviors are fitted with Langmuir adsorption isotherm model. Furthermore, a magnetic solid-phase extraction using Fe3O4@YS-UiO-66-NH2 and HPLC method was developed for the analysis of ALs in spiked samples with the recovery of 89.6-100.8%. In addition, the proposed method was successfully applied in the pharmacokinetics study of berberine, coptisine, and palmatine in the rat. In short, the developed method might be used for high-efficient recognition and determination of ALs in plasma sample, which would also provide a new way to fabricate magnetic functionalized metal-organic framework in separation science.

A review on the bioavailability, bio-efficacies and novel delivery systems for piperine.

As the major naturally occurring alkaloid in pepper with a pungent taste, piperine is known for its beneficial biological functions and therapeutic effects. In this work, the bioavailability and biological activities of piperine were presented and discussed. Novel delivery systems for enhancing the bioavailability of piperine were also reviewed. This study could provide a better understanding of the physiological and biochemical aspects of piperine to be further developed in the food and nutraceutical industries.