scholarly journals Multiple Oral Dosing Pharmacokinetics of Standardized Extract of Centella asiatica ECa 233 and Its Inductive Effect on Efflux Transporters in Rats

2017 ◽  
Vol 4 (02) ◽  
pp. e66-e73 ◽  
Author(s):  
Tosapol Anukunwithaya ◽  
Mayuree Tantisira ◽  
Tsutomu Shimada ◽  
Yoshimichi Sai ◽  
Phisit Khemawoot
Keyword(s):  
Inductive Effect ◽  
Area Under The Curve ◽  
Centella Asiatica ◽  
Pharmacokinetic Data ◽  
Maximum Plasma ◽  
Asiatic Acid ◽  
Multiple Dosing ◽  
Oral Dosing ◽  
Blood Biochemical ◽  
Triterpenoid Glycosides

AbstractECa 233 is a standardized extract of Centella asiatica, characterized as a white powder containing triterpenoid glycosides not less than 80% with a ratio of madecassoside to asiaticoside of 1.5±0.5:1. Although pharmacological and toxicological profiles of ECa 233 have been successively reported, the pharmacokinetic data needed for further therapeutic development are not fully elucidated. This study aimed to investigate the pharmacokinetics of multiple oral dosing of ECa 233 at 100 mg/kg/day for 7 days in rats. Plasma, tissues, urine, and feces were collected from 0 to 24 h after dosing on days 1 and 7. The concentrations of asiaticoside, madecassoside, asiatic acid, and madecassic acid were simultaneously analyzed by liquid chromatography-tandem mass spectrometry. No significant change was observed in physical and blood biochemical parameters of the animals treated with ECa 233 for 7 days. The maximum plasma concentration and area under the curve at day 7 of madecassoside and asiaticoside decreased by 70–80% from day 1. However, both triterpenoid glycosides were extensively distributed and accumulated, resulting in significantly higher concentrations at pharmacologically relevant organs. Madecasssic acid and asiatic acid are major metabolites mainly found in and excreted via feces. Moreover, multiple dosing of ECa 233 increased mRNA expression of Abcb1a and Abcc2 in the small intestine by approximately 2- to 3-fold. This is the first study to identify an inductive effect of a standardized extract of C. asiatica after multiple oral dosing in rats. Potential drug-herb interactions when ECa 233 is coadministered with Abcb1a and Abcc2 substrates calls for further investigations.

scholarly journals Comparison of the Pharmacokinetic Profiles of a Standardized Extract of Centella asiatica and A Mixture of Madecassoside and Asiaticoside in Rats

2018 ◽  
Vol 5 (02) ◽  
pp. e39-e47 ◽  
Author(s):  
Phisit Khemawoot ◽  
Patcharaporn Hengjumrut ◽  
Tosapol Anukunwithaya ◽  
Leng Chang ◽  
Supakit Wongwiwatthananukit ◽  
...  
Keyword(s):  
Herbal Remedy ◽  
Centella Asiatica ◽  
Treated Group ◽  
Herbal Extract ◽  
Asiatic Acid ◽  
Traditional Medicines ◽  
Tropical Plant ◽  
Pharmacokinetic Profiles ◽  
Liquid Chromatography Tandem Mass ◽  
Triterpenoid Glycosides

Abstract Centella asiatica is a tropical plant commonly used as an herbal remedy in traditional medicines in many countries. In an attempt to establish an herbal extract with well-defined characteristics, a standardized extract of C. Asiatica, ECa 233, was developed. This extract contains at least 80% triterpenoid glycosides with the major constituents madecassoside and asiaticoside at a ratio of 1.5±0.5:1. In the present study, comparative pharmacokinetics of ECa 233 with its mixture of madecassoside and asiaticoside were conducted in rats. Following intravenous or oral administration of the test compounds, blood, tissues, urine, and feces were collected for the determination of madecassoside, asiaticoside, and their metabolite levels using liquid chromatography tandem mass spectrometry. Plasma levels of madecassoside and asiaticoside in the ECa 233-treated group were found to be higher than their respective counterparts in the mixture. Madecassoside and asiaticoside in both test formulae appeared to be widely distributed in several organs, and more than 50% of the administered doses were recovered as madecassic acid and asiatic acid in the feces within 24 to 48 h. The results clearly demonstrated the pharmacokinetic advantage of a standardized extract of C. Asiatica, ECa 233, compared with a mixture of madecassoside and asiaticoside at an equivalent amount. Other minor constituents that naturally exist in ECa 233 appeared to positively modulate the pharmacokinetics of its major constituents, resulting in relatively better pharmacokinetic profiles than those from a mixture of pure compounds.

Safety and Pharmacokinetics of Standardized Extract of Centella asiatica (ECa 233) Capsules in Healthy Thai Volunteers: A Phase 1 Clinical Study

Planta Medica ◽  
2019 ◽  
Vol 85 (06) ◽  
pp. 483-490 ◽  
Author(s):  
Phanit Songvut ◽  
Pajaree Chariyavilaskul ◽  
Mayuree Tantisira ◽  
Phisit Khemawoot
Keyword(s):  
Clinical Laboratory ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Centella Asiatica ◽  
Fold Increase ◽  
Repeated Dose ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Asiatic Acid ◽  
Active Metabolites

AbstractThe aim of this study was to investigate the safety and pharmacokinetic profiles of a newly developed, standardized extract of Centella asiatica (ECa 233) capsule in healthy Thai volunteers. This study was designed as an open-labeled, 2-sequence dosage, single- and repeated-dose study investigated under fasting conditions. Plasma concentrations of the parent compounds and their relative acid metabolites were measured and pharmacokinetic parameters were calculated using noncompartmental analysis. Tolerability was assessed based on physical examinations, monitoring of vital signs, clinical laboratory tests, and any observed adverse events. A key finding of this study was that the pharmacokinetics of ECa 233 in healthy volunteers did not correspond with its pharmacokinetics in animal studies. As indicated in human pharmacokinetic parameters, maximum plasma concentration and area under the curve of the parent compounds (madecassoside and asiaticoside) were very low, while their respective metabolites (madecassic acid and asiatic acid) demonstrated higher values. Based on the pharmacokinetic results observed in the dose comparison, accumulation of active metabolites after repeated dose is highly suggestive. In addition, the asiatic acid profile showed 2-fold increase in Cmax and AUC(0–t) after increasing dose from 250 to 500 mg of ECa 233. Lastly, the safety and tolerability evaluation illustrated that single and multiple doses in both 250 and 500 mg oral administration of ECa 233 were well tolerated, and none of the volunteers discontinued their participation due to adverse effects during the study.

Differences in Neuritogenic Activity and Signaling Activation of Madecassoside, Asiaticoside, and Their Aglycones in Neuro-2a cells

Planta Medica ◽  
2018 ◽  
Vol 84 (16) ◽  
pp. 1165-1173 ◽  
Author(s):  
Nonthaneth Nalinratana ◽  
Duangdeun Meksuriyen ◽  
Boonsri Ongpipattanakul
Keyword(s):  
Neurite Outgrowth ◽  
Centella Asiatica ◽  
Camp Response Element Binding ◽  
Asiatic Acid ◽  
Neurite Length ◽  
Creb Phosphorylation ◽  
Creb Activation ◽  
Erk Phosphorylation ◽  
Signaling Activation ◽  
Triterpenoid Glycosides

AbstractMadecassoside (MS) and asiaticoside (AS) along with their aglycones, madecassic acid (MA) and asiatic acid (AA), are considered the major neuroactive triterpenoid constituents of Centella asiatica. In this study, we aimed to compare MS, AS, MA, and AA for their neurite outgrowth activities and mechanisms in Neuro-2a cells. Immunofluorescent cell staining showed MS and AS significantly increased the percentage of neurite-bearing cells (%NBC) and the neurite length with higher potency than MA and AA. The triterpenoid glycosides induced sustained extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) phosphorylation, while their aglycones activated only transient signaling of ERK1/2. Suppression of ERK1/2 activation significantly abolished not only cAMP response element-binding protein (CREB) phosphorylation but also the increment of %NBC and neurite length in MS- and AS-treated cells. Inhibition of ERK phosphorylation did not produce similar blockage of CREB activation and neurite outgrowth in MA- and AA-treated cells. On the other hand, inactivation of protein kinase B (Akt) resulted in a suppression of neurite lengthening in all studied triterpenoids. This is the first study discerning the different signaling pathways of neurite outgrowth activity induced by C. asiatica triterpenoid glycosides and aglycones. Neurite outgrowth activity of the glycosides MS and AS was found to involve the activation of sustained ERK phosphorylation leading to CREB activation, while ERK activation was not associated with MA- and AA-induced neurite outgrowth. In addition, Akt activation was evident to be more involved in neurite elongation process.

Design, Synthesis, Anticonvulsant Activity, Preclinical Study and Pharmacokinetic Performance of N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin- 2-yl] methyl}, 2-[(2-isopropyl-5-methyl) 1-cyclo Hexylidene] Hydrazinecarboxamide

2019 ◽  
Vol 19 (1) ◽  
pp. 31-45
Author(s):  
Meena K. Yadav ◽  
Laxmi Tripathi
Keyword(s):  
Anticonvulsant Activity ◽  
Computational Study ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Area Under The Curve ◽  
Preclinical Study ◽  
In Vivo Studies ◽  
Maximum Plasma ◽  
Seizure Models

Background: N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl] methyl}, 2-[(2- isopropyl-5-methyl) 1-cyclohexylidene] hydrazinecarboxamide QS11 was designed by computational study. It possessed essential pharmacophoric features for anticonvulsant activity and showed good docking with iGluRs (Kainate) glutamate receptor. Methods: QSAR and ADMET screening results suggested that QS11 would possess good potency for anticonvulsant activity. QS11 was synthesised and evaluated for its anticonvulsant activity and neurotoxicity. QS11 showed protection in strychnine, thiosemicarbazide, 4-aminopyridine and scPTZ induced seizure models and MES seizure model. QS11 showed higher ED50, TD50 and PI values as compared to the standard drugs in both MES and scPTZ screen. A high safety profile (HD50/ED50 values) was noted and hypnosis, analgesia, and anaesthesia were only observed at higher doses. No considerable increase or decrease in the concentration of liver enzymes was observed. Optimized QS11 was subjected to preclinical (in-vivo) studies and the pharmacokinetic performance of the sample was investigated. The result revealed that the pharmacokinetic performance of QS11 achieved maximum plasma concentrations (Cmax) of 0.315 ± 0.011 µg/mL at Tmax of 2.0 ± 0.13 h, area under the curve (AUC0-∞) value 4.591 ± 0.163 µg/ml x h, elimination half-life (T1/2) 6.28 ± 0.71 h and elimination rate constant was found 0.110 ± 0.013 h-1. Results and Conclusion: Above evidences indicate that QS11 could serve as a lead for development of new antiepileptic drugs.

scholarly journals Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug–Drug Interaction with Rifampin and Liver Impairment

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 778
Author(s):  
Bettina Gerner ◽  
Oliver Scherf-Clavel
Keyword(s):  
Hepatic Impairment ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Enterohepatic Recirculation ◽  
Maximum Plasma ◽  
Good Precision ◽  
Physiologically Based Pharmacokinetic ◽  
Starting Point ◽  
Physiologically Based

Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug–drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (Cmax) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9–1.2 for AUC and 0.8–1.1 for Cmax). DDI with Rifampin led to a reduction in predicted AUC by 77%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations.

scholarly journals Mitoprotective Effects of Centella asiatica (L.) Urb.: Anti-Inflammatory and Neuroprotective Opportunities in Neurodegenerative Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Jia Hui Wong ◽  
Anna M. Barron ◽  
Jafri Malin Abdullah
Keyword(s):  
Neurodegenerative Disease ◽  
Healthy Aging ◽  
Brain Aging ◽  
Antioxidant Properties ◽  
Centella Asiatica ◽  
Asiatic Acid ◽  
Wide Range ◽  
Anti Inflammatory

Natural products remain a crucial source of drug discovery for accessible and affordable solutions for healthy aging. Centella asiatica (L.) Urb. (CA) is an important medicinal plant with a wide range of ethnomedicinal uses. Past in vivo and in vitro studies have shown that the plant extract and its key components, such as asiatic acid, asiaticoside, madecassic acid and madecassoside, exhibit a range of anti-inflammatory, neuroprotective, and cognitive benefits mechanistically linked to mitoprotective and antioxidant properties of the plant. Mitochondrial dysfunction and oxidative stress are key drivers of aging and neurodegenerative disease, including Alzheimer’s disease and Parkinson’s disease. Here we appraise the growing body of evidence that the mitoprotective and antioxidative effects of CA may potentially be harnessed for the treatment of brain aging and neurodegenerative disease.

scholarly journals Development of Hairy Root Cultures for Biomass and Triterpenoid Production in Centella asiatica

Plants ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 148
Author(s):  
Seungeun Baek ◽  
Jong-Eun Han ◽  
Thanh-Tam Ho ◽  
So-Young Park
Keyword(s):  
Hairy Root ◽  
Mass Production ◽  
Adventitious Roots ◽  
Transformation Efficiency ◽  
Growth Index ◽  
Centella Asiatica ◽  
Asiatic Acid ◽  
Hairy Root Cultures ◽  
Root Cultures ◽  
Petiole Explants

Centella asiatica (Apiaceae) is a tropical/subtropical medicinal plant, which contains a variety of triterpenoids, including madecassoside, asiaticoside, madecassic acid, and asiatic acid. In this study, we tested the efficiency of hairy root (HR) induction in C. asiatica from leaf and petiole explants. Leaves and petioles collected from C. asiatica plants were suspended in agro-stock for 30 min and co-cultured with Agrobacterium rhizogenes for 3 days to induce HR formation. The transformation efficiency of leaf and petiole explants was approximately 27% and 12%, respectively. A total of 36 HR lines were identified by PCR-based amplification of rol genes, and eight of these lines were selected for further analysis. Among all eight HR lines, the petiole-derived lines HP4 and HP2 displayed the highest growth index (37.8) and the highest triterpenoids concentration (46.57 mg∙g−1), respectively. Although triterpenoid concentration was >2-fold higher in leaves than in petioles of C. asiatica plants, the accumulation of triterpenoids in petiole-derived HR cultures was 1.4-fold higher than that in leaf-derived HR cultures. Additionally, in both leaf- and petiole-derived HR cultures, terpenoid production was higher in HRs than in adventitious roots. These results demonstrate that the triterpenoid content in the explant does not affect the triterpenoid content in the resultant HRs. The HR culture of C. asiatica could be scaled up to enable the mass production of triterpenoids in bioreactors for the pharmaceutical and cosmetic industries.

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