Managing the dysregulated host response to infection remains a major challenge in sepsis care. Chinese treatment guideline recommends adding Xue Bi Jing, a five-herb medicine, to antibioticbased sepsis care. Although ...Managing the dysregulated host response to infection remains a major challenge in sepsis care. Chinese treatment guideline recommends adding Xue Bi Jing, a five-herb medicine, to antibioticbased sepsis care. Although adding Xue Bi Jing further reduced 28-day mortality via modulating the host response, pharmacokinetic herbedrug interaction is a widely recognized issue that needs to be studied.Building on our earlier systematic chemical and human pharmacokinetic investigations of Xue Bi Jing, we evaluated the degree of pharmacokinetic compatibility for Xue Bi Jing/antibiotic combination based on mechanistic evidence of interaction risk. Considering both Xue Bi Jing-antibiotic and antibiotic-Xue Bi Jing interaction potential, we integrated informatics-based approach with experimental approach and developed a compound pair-based method for data processing. To reflect clinical reality, we selected for study Xue Bi Jing compounds bioavailable for drug interactions and 45 antibiotics commonly used in sepsis care in China. Based on the data of interacting with drug metabolizing enzymes and transporters, no Xue Bi Jing compound could pair, as perpetrator, with the antibiotics. Although some antibiotics could,due to their inhibition of uridine 50-diphosphoglucuronosyltransferase 2 B15, organic anion transporters1/2 and/or organic anion-transporting polypeptide 1 B3, pair with senkyunolide I, tanshinol and salvianolic acid B, the potential interactions(resulting in increased exposure) are likely desirable due to these Xue Bi Jing compounds’ low baseline exposure levels. Inhibition of aldehyde dehydrogenase by 7 antibiotics probably results in undesirable reduction of exposure to protocatechuic acid from Xue Bi Jing.Collectively, Xue Bi Jing/antibiotic combination exhibited a high degree of pharmacokinetic compatibility at clinically relevant doses. The methodology developed can be applied to investigate other drug combinations.展开更多
Psoraleae Fructus(the dried fruits of Psoralea corylifolia), one of the most frequently used Chinese herbs in Asian countries, has a variety of biological activities. In clinical settings, Psoraleae Fructus or Psorale...Psoraleae Fructus(the dried fruits of Psoralea corylifolia), one of the most frequently used Chinese herbs in Asian countries, has a variety of biological activities. In clinical settings, Psoraleae Fructus or Psoraleae Fructus-related herbal medicines frequently have been used in combination with a number of therapeutic drugs for the treatment of various human diseases, such as leukoderma, rheumatism and dysentery. The use of Psoraleae Fructus in combination with drugs has aroused concern of the potential risks of herb-drug interactions(HDI) or herb-endobiotic interactions(HEI). This article reviews the interactions between human drug-metabolizing enzymes and the constituents of Psoraleae Fructus;the major constituents in Psoraleae Fructus, along with their chemical structures and metabolic pathways are summarized, and the inhibitory and inductive effects of the constituents in Psoraleae Fructus on human drug-metabolizing enzymes(DMEs), including target enzyme(s), its modulatory potency, and mechanisms of action are presented. Collectively, this review summarizes current knowledge of the interactions between the Chinese herb Psoraleae Fructus and therapeutic drugs in an effort to facilitate its rational use in clinical settings, and especially to avoid the potential risks of HDI or HEI through human DMEs.展开更多
Objective:To determine the antimicrobial activity of rosemary(Rosmarinus of ficinalis L.) and to investigate the synergistic effects of this extract combined with ceforuxime against methicillinresistant Staphylococcus...Objective:To determine the antimicrobial activity of rosemary(Rosmarinus of ficinalis L.) and to investigate the synergistic effects of this extract combined with ceforuxime against methicillinresistant Staphylococcus aureus(MRSA).Methods:The inhibitory and bactericidal activities of rosemary ethanol extract,alone and in combination with cefuroxime,were studied.Results:The minimum inhibitory concentrations(MICs) of the ethanol extract of rosemary were in the range of 0.39-3.13 mg/mL.The minimum bactericidal concentrations(MBCs) were usually equal to or double that MICs.The antimicrobial activity of combinations of the ethanol extract of rosemary and cefuroxime indicated their synergistic effects against all MRSAs.Conclusions:The present work clearly demonstrates that rosemary has a key role in the elevation of susceptibility toβ-lactams.展开更多
Isochlorogenic acid A(ICQA), which has anti-inflammatory, hepatoprotective, and antiviral properties, is commonly presented in fruits, vegetables, coffee, plant-based food products, and herbal medicines. These herbal ...Isochlorogenic acid A(ICQA), which has anti-inflammatory, hepatoprotective, and antiviral properties, is commonly presented in fruits, vegetables, coffee, plant-based food products, and herbal medicines. These herbal medicines are usually used in combination with other medicines in the clinic. However, little is known about the regulatory effects of ICQA on drug-metabolizing enzymes and the herb-drug interactions. In the present study, we evaluated the inhibitory potentials of ICQA on CYP1A2, CYP2C9,CYP2C19, CYP3A4, CYP2D6, and CYP2E1 in vitro based on a cocktail approach. The P450 and UGT activities in mice treated with ICQA for a prolonged period were also determined. Our results demonstrated that ICQA exhibited a weak inhibitory effect on CYP2C9 in human liver microsomes with IC_(50) being 57.25 μmol·L^(-1) and Ki being 26.77 μmol·L^(-1). In addition, ICQA inhibited UGT1A6 activity by 25%, in the mice treated with ICQA(i.p.) at 30 mg·kg^(-1)for 14 d, compared with the control group. Moreover, ICQA showed no mechanism-based inhibition on CYP2C9 or UGT1A6. In conclusion, our results further confirm a safe use of ICQA in clinical practice.展开更多
In the past century, as medical research has become increasingly precise, it has become clear that the incidence and progression of many diseases involve multiple factors and pathologies; this is particularly true for...In the past century, as medical research has become increasingly precise, it has become clear that the incidence and progression of many diseases involve multiple factors and pathologies; this is particularly true for the degenerative and metabolic diseases facing industrialized societies. At the same time, it becomes increasingly clear that single-target action drugs cannot effectively treat these diseases. Researchers are looking toward the chemical industry as well as traditional herbal medicines to find multi-target interventions. Thus, a new era in drug discovery has begun. Specifically, three approaches have proven effective in seeking multi-target drugs. These are： （1） designing drugs with multiple components; （2） discovering drugs through the study of synergistic compound-compound interactions in medicinal herbs or among chemical drugs and herbal components; and （3） developing drugs to tackle complex multi-component diseases. The authors conclude that there is an increasing need for multi-component remedies to treat the complex chronic diseases afflicting modern populations. Given this situation and the growing body of evidence that these new approaches are effective, multi-target intervention appears to have great potential for discovering, designing, and developing effective new drugs for today＇s diseases.展开更多
With the increasing enhancement of people＇s awareness of self-care,the voice for humans to return to nature is growing louder and louder.Drugs with natural plants as raw materials are increasingly favored by people a...With the increasing enhancement of people＇s awareness of self-care,the voice for humans to return to nature is growing louder and louder.Drugs with natural plants as raw materials are increasingly favored by people all over the world for their unique advantages in preventing and curing diseases, rehabilitation and health care,especially in Europe,展开更多
Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has spread worldwide.Effective treatments against COVID-19 remain urgently in need although vaccination signific...Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has spread worldwide.Effective treatments against COVID-19 remain urgently in need although vaccination significantly reduces the incidence,hospitalization,and mortality.At present,antiviral drugs including Nirmatrelvir/Ritonavir(Paxlovid^(TM)),Remdesivir,and Molnupiravir have been authorized to treat COVID-19 and become more globally available.On the other hand,traditional Chinese medicine(TCM)has been used for the treatment of epidemic diseases for a long history.Currently,various TCM formulae against COVID-19 such as Qingfei Paidu decoction,Xuanfei Baidu granule,Huashi Baidu granule,Jinhua Qinggan granule,Lianhua Qingwen capsule,and Xuebijing injection have been widely used in clinical practice in China,which may cause potential herb-drug interactions(HDIs)in patients under treatment with antiviral drugs and affect the efficacy and safety of medicines.However,information on potential HDIs between the above anti-COVID-19 drugs and TCM formulae is lacking,and thus this work seeks to summarize and highlight potential HDIs between antiviral drugs and TCM formulae against COVID-19,and especially pharmacokinetic HDIs mediated by metabolizing enzymes and/or transporters.These well-characterized HDIs could provide useful information on clinical concomitant medicine use to maximize clinical outcomes and minimize adverse and toxic effects.展开更多
The combination of herbs and drugs is one of the most important approaches in the prevention and treatment of diseases in the integrated traditional and Western medicine （ITWM）. While most medical practices have pro...The combination of herbs and drugs is one of the most important approaches in the prevention and treatment of diseases in the integrated traditional and Western medicine （ITWM）. While most medical practices have proved that the combination of herbs and drugs led to a clinical efficacy that was often superior to merely using only one of them; results from some studies have triggered adverse reactions to such an approach. Since few herb-drug interaction studies were carried out during treatments combining herbs and drugs, it really restricts the development of treatment and treatment theory of the combination of herbs and drugs. Given that herb-drug interactions may occur through the main pathway of cytochrome P450 enzymes and transporters; then to exhaustively study the role and impact of herbs in drug metabolism, as well as to establish a corresponding database, is of greatsignificance for guiding the rational combination of herbs and drugs. When the herb-drug interaction information platform is implemented, we would get at ease a reasonable herb-drug prescription to achieve a better outcome, reduce dosage of some expensive drugs preserving the same efficacy, or even reduce some side effects of particular drugs; which might also promote the dynamic combination of Chinese and Western medicine, and accelerate the theory development of ITWM.展开更多
In the present study, the potential inhibition behaviors of notoginseng total saponins(NS), safflower total flavonoids(SF), and their combination(CNS) towards three major isoforms of UDP-glucuronosyltransferases(UGTs)...In the present study, the potential inhibition behaviors of notoginseng total saponins(NS), safflower total flavonoids(SF), and their combination(CNS) towards three major isoforms of UDP-glucuronosyltransferases(UGTs) in human liver microsomes(HLMs) were investigated to study the mechanism of the synergistic effect of CNS.Etoposide, trifluoperazine and azidothymidine were selected as the probe drugs to elucidate the activities of UGT1A1, 1A4 and 2B7 by UPLC-MS/MS method, respectively.The results showed that CNS, NS and SF significantly inhibited the activities of UGT1A1, 1A4 and 2B7(P<0.05) with the IC_(50) values less than 30 mg/mL.Furthermore, the inhibitory effects of CNS towards UGT1A1, 1A4 and 2B7 were stronger than those of NS and SF(P<0.05).In conclusion, the combination of NS and SF could increase their inhibitory effects on UGT1A1, 1A4 and 2B7 activities in HLMs and might be conducive to reduce the phase II metabolism of the effective constituents in CNS.The potential herb-drug interactions of CNS based on UGT enzymes provided a useful experimental basis for its further research and development.展开更多
Objective：To assess the effects of traditional herbal formulae Sijunzi Decoction（四君子汤,Sagunja-tang,SJZD）,Siwu Decoction（四物汤,Samul-tang,SWD）,Bawu Decoction（八物汤,Palmul-tang,BWD）and Shiquan Dabu Decoctio...Objective：To assess the effects of traditional herbal formulae Sijunzi Decoction（四君子汤,Sagunja-tang,SJZD）,Siwu Decoction（四物汤,Samul-tang,SWD）,Bawu Decoction（八物汤,Palmul-tang,BWD）and Shiquan Dabu Decoction（十全大补汤,Sipjeondaebo-tang,SDD）on the activities of human cytochrome P450（CYP450）,a drug-metabolizing enzyme.Methods：Herbal formula water extracts were filtered and lyophilized after the powder extracts were dissolved in distilled water.The activities of major human CYP450isozymes（CYP3A4,CYP2C19,CYP2D6 and CYP2E1）were measured using in vitro fluorescence-based enzyme assays.The inhibitory effects of the herbal formulas on the activities of CYP450 were characterized as half maximal inhibition concentration（IC50）values.Results：All the tested herbal formulae inhibited CYP2C19activity（IC50：SJZD,83.28μg/m L;SWD,235.54μg/m L;BWD,166.82μg/m L;SDD,178.19μg/m L）;SJZD（IC50=196.46μg/m L）,SWD（IC50=333.42μg/m L）and SDD（IC50=163.42μg/m L）inhibited CYP2E1-mediated metabolism;whereas BWD exhibited comparatively weak inhibition of CYP2E1（IC50=501.78μg/m L）.None of the four herbal formulas significantly affected CYP3A4 or CYP2D6.Conclusions：These results suggest that SJZD,SWD,BWD and SDD could potentially inhibit the metabolism of co-administered synthetic drugs whose primary route of elimination is via CYP2C19.In addition,clinically relevant pharmacokinetic interactions could occur when SJZD,SWD or SDD is co-administered with drugs metabolized by CYP2E1.Our findings provide information for the safety and effective clinical use of these four classic herbal formulas.展开更多
Objective： To evaluate the potential pharmacokinetic interactions of the anticancer agent gefitinib （Iressae） and the oriental medications Guipi Decoction （归脾汤, GPD, Guibi-tang in Korean） and Bawu Decoction ...Objective： To evaluate the potential pharmacokinetic interactions of the anticancer agent gefitinib （Iressae） and the oriental medications Guipi Decoction （归脾汤, GPD, Guibi-tang in Korean） and Bawu Decoction （八物汤, BWD, Palmul-tang in Korean）. Methods： Methylceliulose （MC, control）, GPD （1,200 mg/kg）, or BWD （6,000 mg/kg） was orally administered to rats either as a single dose or multiple doses prior to gefitinib administration. To examine the effects of a single dose of the herbal medicines, gefitinib （10 mg/kg） was orally administered after 5 min or 1 h of MC or the herbal medicine pretreatments. To examine the effects of the multiple doses of the herbal medicines, gefltinib （10 mg/kg） was orally administered following 7 consecutive days of the administration of MC or each herbal medicine. The plasma concentrations of gefitinib were determined with liquid chromatography-tandem mass spectrometry assay. The plasma concentration-time profiles of gefitinib were analyzed with a noncompartmental analysis. Results： Gefitinib was rapidly absorbed and showed a mono- exponential decline with an elimination half-life of 3.7-4.1 h. The pharmacokinetics of gefitinib was not affected by GPD pretreatment. However, a significantly lower maximum plasma concentration （Crux, P〈0.05） and area under the curve （P〈0.05）, and a delayed time to reach Cmax （Tmax, P〈0.01） were observed in both single- and multiple- dose BWD-pretreated rats compared with the control rats. Conclusions： BWD and not GPD might delay and interfere with gefitinib absorption. Further evaluations of the clinical significance of these findings are needed.展开更多
In the 21st century, the public are more informed, mainly via the Internet, about health and medical products and have become more knowledgeable about matters relating to their health conditions and well-being in curi...In the 21st century, the public are more informed, mainly via the Internet, about health and medical products and have become more knowledgeable about matters relating to their health conditions and well-being in curing and preventing illnesses. They often self-medicate themselves with various health products and over-the-counter （OTC） medicines apart from prescribed pharmaceutical drugs （PD）. Some of those non-prescribed products may have doubtful quality control and contain harmful additives or unchecked ingredients; thus their usefulness is in doubt. The increasing popularity world-wide of using Chinese medicines （CM） and related OTC functional products has raised concerns over their concomitant use with PD and the consequential adverse effects. In most cases the alleged causes of adverse effects are linked with herbal sources, although the authorised information on the interactions between CM-PD is not plentiful in the literature. There is an urgent need for such a data base. The future professionals in health and medical care should be knowledgeable or aware of what their patients have been taking or given. In actual practice the patients may receive both treatments intentionally or unintentionally, with or without the awareness of the practitioner. In these situations a reliable database for interactions between CM-PD will be extremely useful for consultation when treatment problems appear or during emergency situations. Their combining of medications may be involved with possible outcomes of adverse reactions or beneficial effects. Such a database will be welcomed by both practitioners of herbal medicines and orthodox medicine practitioners in the emerging trend of integrative medicine. The author has been involved in various research projects of basic and clinical aspects in mainly CM among other herbal and PD. Examples will be given largely on those related to these disciplines as illustrations in this overview.展开更多
Objective： The combination effect of Piperbetle （PB） and 5-fluorouracil （5-FU） in enhancing the cytotoxic potential of 5-FU in inhibiting the growth of colon cancer cells was investigated. Methods： HT29 and HCT1...Objective： The combination effect of Piperbetle （PB） and 5-fluorouracil （5-FU） in enhancing the cytotoxic potential of 5-FU in inhibiting the growth of colon cancer cells was investigated. Methods： HT29 and HCT116 cells were subjected to 5-FU or PB treatment. 5-FU and PB were then combined and their effects on both cell lines were observed after 24 h of treatment. PB-5-FU interaction was elucidated by isobologram analysis. Apoptosis features of the treated cells were revealed by annexin V/PI stain. High-performance liquid chromatography （HPLC） was performed to exclude any possible chemical interaction between the compounds. Results： In the presence of PB extract, the cytotoxicity of 5-FU was observed at a lower dose （IC^0 12.5 pmol/L） and a shorter time （24 h） in both cell lines. Both cell lines treated with 5-FU or PB alone induced a greater apoptosis effect compared with the combination treatment. Isobologram analysis indicated that PB and 5-FU interacted synergistically and antagonistically in inhibiting the growth of HT29 and HCT116 cells, respectively. Conclusions： In the presence of PB, a lower dosage of 5-FU is required to achieve the maximum drug effect in inhibiting the growth of HT29 cells. However, PB did not significantly reduce 5-FU dosage in HCT116 cells. Our result showed that this interaction may not solely contribute to the apoptosis pathway.展开更多
Objectives: Radix Polygoni Multiflori Praeparata (RPMP) and Dioscorea Bulbifera Rhizomes (DBR) are used in Chinese herbal medicine and have been frequently reported for adverse reactions on liver. In this research, we...Objectives: Radix Polygoni Multiflori Praeparata (RPMP) and Dioscorea Bulbifera Rhizomes (DBR) are used in Chinese herbal medicine and have been frequently reported for adverse reactions on liver. In this research, we aimed to evaluate in vivo effects of RPMP and DBR on rat cytochrome P450 enzymes (CYP1A2, CYP2E1 and CYP3A2) with their respective substrates as probes. Methods: Rats were orally administered RPMP, DBR and RPMP/DBR combination at 12, 10 and (12 + 10) g/kg, respectively, or saline as a control, once daily for 7 days. Thereafter, a cocktail containing 10 mg/kg caffeine, 20 mg/kg chlorzoxazone and 10 mg/kg dapsone was tail vein injected to rats. At defined time points, plasma drug concentrations were simultaneously evaluated by HPLC. Pharmacokinetic parameters simulated by DAS software were used to assess RPMP and/or DBR effects on cytochrome P450 enzymes activity. ANOVA and Dunnett’s test were used for data analysis. Results: Caffeine metabolism was enhanced in RPMP animals and reduced after pretreatment with DBR, but no effect was observed in RPMP/DBR combination group. Chlorzoxazone and dapsone metabolism was enhanced in both RPMP and DBR groups and consequently in combination group. The data suggested that RPMP independently induces rat CYP1A2, CYP2E1 and CYP3A2 activity, while DBR independently inhibits activity of rat CYP1A2 and induces that of CYP2E1 and CYP3A2. RPMP/DBR combination showed no significant benefit compared with the two drugs alone and even showed a neutralized effect in CYP1A2 activity. Conclusions: Caution is needed when RPMP and/or DBR are co-administered with drugs metabolized by human CYP1A2, CYP2E1 and CYP3A4.展开更多
Background and aims:The herbal supplement Gancao,also known as licorice,belongs to the genus Glycyrrhiza and has been used worldwide for its hepatoprotective effect.Recent studies have raised concerns about potential ...Background and aims:The herbal supplement Gancao,also known as licorice,belongs to the genus Glycyrrhiza and has been used worldwide for its hepatoprotective effect.Recent studies have raised concerns about potential herb-drug interactions associated with Gancao via pregnane X receptor(PXR)-mediated induction of hepatic cytochrome P4503A4(CYP3A4).The current work aimed to determine the phytochemicals in Gancao that activate PXR and induce CYP3A4.Methods:DPX2 cells were used for cell-based PXR reporter assays.The phytochemicals in Gancao extract were identified using a metabolomics approach.The effects of PXR activators identified from in vitro studies were further investigated in PXR-and CYP3A4-humanized mouse models.Results:Gancao was verified to be a PXR-activating herb.Two major phytochemicals in Gancao,gly-cyrrhizin(GZ)and glycyrrhetinic acid(GA),did not activate PXR in the cell-based reporter assays.However,glabridin was shown to activate PXR in a dose-dependent manner.In vivo studies confirmed that GZ is not a PXR activator and glabridin is a weak PXR activator.Although GA did not active PXR in vitro,it induced CYP3A4 expression in a PXR-dependent manner in the PXR-and CYP3A4-humanized mice.展开更多
Angelica dahurica is commonly referred to as ‘Baizhi’ in China and has been noted for its therapeutic significance. The major active ingredients of Angelica dahurica is coumarin, which is reported as a kind of poten...Angelica dahurica is commonly referred to as ‘Baizhi’ in China and has been noted for its therapeutic significance. The major active ingredients of Angelica dahurica is coumarin, which is reported as a kind of potent inhibitor of cytochrome P450 enzymes (CYP450s). The aim of this study was to investigate the inhibition of CYP3A enzymes by total coumarin extract (TCE) obtained from dried root of Angelica dahurica by using in situ single pass intestinal perfusion (SPIP) and in situ liver perfusion in rats. When midazolam (MDZ) which is a substrate of CYP3A co-perfused with TCE (198 μg/mL) from Baizhi in duodenum and ileum segments, the Peff of MDZ has increased significantly compared with the MDZ single perfused group (p 0.05) (n = 6). During in situ liver perfusion study, the results demonstrated that, 3 days oral administration of TCE obtained from Baizhi could significantly reduce the elimination rate of MDZ in the perfusate (p Angelica dahurica extract co-administrated with drugs which are the substrates of CYP3A, much more attention should be paid rather than that of other CYP450 enzymes. These findings may facilitate in predicting possible herb-drug interactions (HDIs) when Angelica dahurica is used in combination with other drugs, and decrease the incidence of the CYP450-mediated HDIs.展开更多
OBJECTIVE： Consuming botanical dietary supplements or herbal drugs along with prescription drugs may lead to potential pharmacokinetic-pharmacodynamic（PK-PD） herb-drug interactions（HDI）. The present study focuses...OBJECTIVE： Consuming botanical dietary supplements or herbal drugs along with prescription drugs may lead to potential pharmacokinetic-pharmacodynamic（PK-PD） herb-drug interactions（HDI）. The present study focuses on the importance of and novel approach for assessing HDI in integrative medicine with case examples of two frequently-used Ayurvedic Rasayana botanicals.METHODS： The aqueous extracts of Asparagus racemosus（ARE） and Gymnema sylvester（GSE） were prepared as per Ayurvedic Pharmacopoeia of India. Chemoprofiling of these extracts was done using high-performance liquid chromatography（HPLC）. Additionally, ARE was characterized for the presence of shatavarins IV and I using HPLC ＆ mass spectroscopy respectively. Effects of ARE and GSE were investigated on rat liver microsome using testosterone probe drug assay. The changes in formation of metabolite（6-β hydroxy testosterone） were monitored on incubation of testosterone alone, testosterone with ketoconazole, ARE and GSE using HPLC. Half inhibitory concentration（IC50） was used to predict plausible HDI.RESULTS： ARE and GSE showed no inhibition with IC50 values 〉1 000 μg/m L while the standard inhibitor ketoconazole completely abolished CYP3A4-dependent activity at 0.531 μg/m L and IC50 was found to be 0.036 μg/m L.CONCLUSION： ARE and GSE prepared as per Ayurvedic Pharmacopoeia of India were found to be safe for CYP3A4-mediated inhibitory HDI in rats. Our in vitro study suggests the need of further in vivo investigation for HDI in order to provide clinical relevance.展开更多
The present study was intended to discover the interaction between Ocimum sanctum(O. sanctum) and Glimepiride, a sulfonylurea derivative used in the treatment of type-2 diabetes, in diabetic rats to suggest an alterat...The present study was intended to discover the interaction between Ocimum sanctum(O. sanctum) and Glimepiride, a sulfonylurea derivative used in the treatment of type-2 diabetes, in diabetic rats to suggest an alteration in the dose of Glimepiride in case of hypoglycaemia. LD50 studies for the aqueous extract of O. sanctum leaf were carried out in albino mice up to the dose level of 2000 mg/kg. O. sanctum at low, medium and high doses(100, 200 and 400 mg/kg, per oral), respectively and Glimepiride ?(half) therapeutic dose, therapeutic dose and 2 time therapeutic dose(0.036, 0.072 and 0.144 mg/200 g, per oral) were selected. After the treatment with O. sanctum and Glimepiride as single doses and in various combinations of these two drugs in streptozotocin-induced diabetic rats serum glucose levels in all the groups were analysed by the glucose oxidase-peroxidase method. When administered alone as single doses both aqueous extract of O. sanctum leaf and Glimepiride produced a significant anti-diabetic effect in diabetic rats. The anti-diabetic effect observed with combination of aqueous extract of O. sanctum leaf and Glimepiride was significant and more when compared to either of the drugs given alone. There was a definite interaction that necessitates dose readjustment of Glimepiride and further glucose levels are to be frequently monitored to avoid complication of hypoglycemic condition with aqueous extract of O. sanctum leaf and Glimepiride combination.展开更多
BACKGROUND： P-glycoprotein （P-gp） is a 170-kDa membrane protein. It provides a barrier function and help to excrete toxins from the body as a transporter. Some bioflavonoids have been shown to block P-gp activity. ...BACKGROUND： P-glycoprotein （P-gp） is a 170-kDa membrane protein. It provides a barrier function and help to excrete toxins from the body as a transporter. Some bioflavonoids have been shown to block P-gp activity. OBJECTIVE： To evaluate the important amino acid residues within nucleotide binding domain 1 （NBD l） of P-gp that play a key role in molecular interactions with flavonoids using structure-based pharmacophore model. METHODS： In the molecular docking with NBD 1 models, a putative binding site of flavonoids was proposed and compared with the site for ATP. The binding modes for ligands were achieved using LigandScout to generate the P-gp-flavonoid pharmacophore models. RESULTS： The binding pocket for flavonoids was investigated and found these inhibitors compete with the ATP for binding site in NBD1 including the NBD1 amino acid residues identified by the in silico techniques to be involved in the hydrogen bonding and van der Waals （hydrophobic） interactions with flavonoids. CONCLUSION： These flavonoids occupy with the same binding site of ATP in NBD1 proffering that they may act as an ATP competitive inhibitor.展开更多
OBJECTIVE:To investigate the influence of Yin-tonification herbal formulas Jaeumganghwa-tang(Ziyin Jianghuo Tang,JEGHT),Ssanghwa-tang(Shuanghe Tang,SHT) and Yukmijihwang-tang(Liuwei Di huang Tang,YMJHT) on the activit...OBJECTIVE:To investigate the influence of Yin-tonification herbal formulas Jaeumganghwa-tang(Ziyin Jianghuo Tang,JEGHT),Ssanghwa-tang(Shuanghe Tang,SHT) and Yukmijihwang-tang(Liuwei Di huang Tang,YMJHT) on the activities of human major cytochrome P450(CYP450 s) and UDP-glucuronosyltransferases isozymes(UGTs) in vitro.METHODS:The activities of CYP450 s(CYP1 A2,CYP3 A4,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6 and CYP2 E1) and UGTs(UGT1 A1,UGT1 A4 and UGT2 B7)were assessed using in vitro fluorescence-and luminescence-based enzyme assays,respectively.The effects of herbal formulas on the activities of CYP450 s and UGTs were presented as IC50 values.RESULTS:JEGHT showed the potent inhibition of the CYP2 D6 activity,with weak inhibition on the activities of CYP1 A2,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 E1,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7.SHT inhibited the activities of CYP1 A2 and CYP2 E1,whereas the negligible inhibition of the activities of CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7 through SHT was observed.YMJHT inhibited CYP2 E1 activity,with a negligible inhibition on the activities of CYP1 A2,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7.CONCLUSION:These findings provide information about the potential interactions between three Yin-tonification herbal formulas and conventional drugs.展开更多
基金funded by grants from the National Science&Technology Major Project of China “Key New Drug Creation and Manufacturing Program”(2017ZX09301012006)the National Basic Research Program of China(2012CB518403)+1 种基金the National Natural Science Foundation of China(81503345)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12050306)
文摘Managing the dysregulated host response to infection remains a major challenge in sepsis care. Chinese treatment guideline recommends adding Xue Bi Jing, a five-herb medicine, to antibioticbased sepsis care. Although adding Xue Bi Jing further reduced 28-day mortality via modulating the host response, pharmacokinetic herbedrug interaction is a widely recognized issue that needs to be studied.Building on our earlier systematic chemical and human pharmacokinetic investigations of Xue Bi Jing, we evaluated the degree of pharmacokinetic compatibility for Xue Bi Jing/antibiotic combination based on mechanistic evidence of interaction risk. Considering both Xue Bi Jing-antibiotic and antibiotic-Xue Bi Jing interaction potential, we integrated informatics-based approach with experimental approach and developed a compound pair-based method for data processing. To reflect clinical reality, we selected for study Xue Bi Jing compounds bioavailable for drug interactions and 45 antibiotics commonly used in sepsis care in China. Based on the data of interacting with drug metabolizing enzymes and transporters, no Xue Bi Jing compound could pair, as perpetrator, with the antibiotics. Although some antibiotics could,due to their inhibition of uridine 50-diphosphoglucuronosyltransferase 2 B15, organic anion transporters1/2 and/or organic anion-transporting polypeptide 1 B3, pair with senkyunolide I, tanshinol and salvianolic acid B, the potential interactions(resulting in increased exposure) are likely desirable due to these Xue Bi Jing compounds’ low baseline exposure levels. Inhibition of aldehyde dehydrogenase by 7 antibiotics probably results in undesirable reduction of exposure to protocatechuic acid from Xue Bi Jing.Collectively, Xue Bi Jing/antibiotic combination exhibited a high degree of pharmacokinetic compatibility at clinically relevant doses. The methodology developed can be applied to investigate other drug combinations.
基金supported by the NSF of China(Nos.81922070,81973286,81773687)the National Key Research and Development Program of China(No.2017YFC1700200,2017YFC1702000)+3 种基金Program of Shanghai Academic/Technology Research Leader(No.18XD1403600)Shuguang Program(No.18SG40)Program for applied basic research of Qinghai Provincial Science and Technology Department(No.2017-ZJ-713)Program for Innovative Leading Talents of Qinghai Province(2018&2019)
文摘Psoraleae Fructus(the dried fruits of Psoralea corylifolia), one of the most frequently used Chinese herbs in Asian countries, has a variety of biological activities. In clinical settings, Psoraleae Fructus or Psoraleae Fructus-related herbal medicines frequently have been used in combination with a number of therapeutic drugs for the treatment of various human diseases, such as leukoderma, rheumatism and dysentery. The use of Psoraleae Fructus in combination with drugs has aroused concern of the potential risks of herb-drug interactions(HDI) or herb-endobiotic interactions(HEI). This article reviews the interactions between human drug-metabolizing enzymes and the constituents of Psoraleae Fructus;the major constituents in Psoraleae Fructus, along with their chemical structures and metabolic pathways are summarized, and the inhibitory and inductive effects of the constituents in Psoraleae Fructus on human drug-metabolizing enzymes(DMEs), including target enzyme(s), its modulatory potency, and mechanisms of action are presented. Collectively, this review summarizes current knowledge of the interactions between the Chinese herb Psoraleae Fructus and therapeutic drugs in an effort to facilitate its rational use in clinical settings, and especially to avoid the potential risks of HDI or HEI through human DMEs.
文摘Objective:To determine the antimicrobial activity of rosemary(Rosmarinus of ficinalis L.) and to investigate the synergistic effects of this extract combined with ceforuxime against methicillinresistant Staphylococcus aureus(MRSA).Methods:The inhibitory and bactericidal activities of rosemary ethanol extract,alone and in combination with cefuroxime,were studied.Results:The minimum inhibitory concentrations(MICs) of the ethanol extract of rosemary were in the range of 0.39-3.13 mg/mL.The minimum bactericidal concentrations(MBCs) were usually equal to or double that MICs.The antimicrobial activity of combinations of the ethanol extract of rosemary and cefuroxime indicated their synergistic effects against all MRSAs.Conclusions:The present work clearly demonstrates that rosemary has a key role in the elevation of susceptibility toβ-lactams.
基金supported by Natural Science Foundation of Jiangsu province for outstanding youth scholar(No.BK2012026)National Natural Science Foundation of China(Nos.81430091,81325025,and 81273586)
文摘Isochlorogenic acid A(ICQA), which has anti-inflammatory, hepatoprotective, and antiviral properties, is commonly presented in fruits, vegetables, coffee, plant-based food products, and herbal medicines. These herbal medicines are usually used in combination with other medicines in the clinic. However, little is known about the regulatory effects of ICQA on drug-metabolizing enzymes and the herb-drug interactions. In the present study, we evaluated the inhibitory potentials of ICQA on CYP1A2, CYP2C9,CYP2C19, CYP3A4, CYP2D6, and CYP2E1 in vitro based on a cocktail approach. The P450 and UGT activities in mice treated with ICQA for a prolonged period were also determined. Our results demonstrated that ICQA exhibited a weak inhibitory effect on CYP2C9 in human liver microsomes with IC_(50) being 57.25 μmol·L^(-1) and Ki being 26.77 μmol·L^(-1). In addition, ICQA inhibited UGT1A6 activity by 25%, in the mice treated with ICQA(i.p.) at 30 mg·kg^(-1)for 14 d, compared with the control group. Moreover, ICQA showed no mechanism-based inhibition on CYP2C9 or UGT1A6. In conclusion, our results further confirm a safe use of ICQA in clinical practice.
基金Supported by Hong Kong Baptist University(RC/08-09/GEN-043)
文摘In the past century, as medical research has become increasingly precise, it has become clear that the incidence and progression of many diseases involve multiple factors and pathologies; this is particularly true for the degenerative and metabolic diseases facing industrialized societies. At the same time, it becomes increasingly clear that single-target action drugs cannot effectively treat these diseases. Researchers are looking toward the chemical industry as well as traditional herbal medicines to find multi-target interventions. Thus, a new era in drug discovery has begun. Specifically, three approaches have proven effective in seeking multi-target drugs. These are： （1） designing drugs with multiple components; （2） discovering drugs through the study of synergistic compound-compound interactions in medicinal herbs or among chemical drugs and herbal components; and （3） developing drugs to tackle complex multi-component diseases. The authors conclude that there is an increasing need for multi-component remedies to treat the complex chronic diseases afflicting modern populations. Given this situation and the growing body of evidence that these new approaches are effective, multi-target intervention appears to have great potential for discovering, designing, and developing effective new drugs for today＇s diseases.
文摘With the increasing enhancement of people＇s awareness of self-care,the voice for humans to return to nature is growing louder and louder.Drugs with natural plants as raw materials are increasingly favored by people all over the world for their unique advantages in preventing and curing diseases, rehabilitation and health care,especially in Europe,
基金supported by the National Natural Science Foundation of China(grants 82025034 and 81973392 to Huichang Bi.And grants 82274193 and 82074110 to Ling Ye)the Open Project of State Key Laboratory of Natural Medicines(grant SKLNMKF202209 to Ling Ye,China)+2 种基金the Shenzhen Science and Technology Program(No.KQTD20190929174023858 to Huichang Bi,China)Guangdong Basic and Applied Basic Research Foundation(2023A1515012859 to Shicheng Fan,China)Guangdong Medical Research Foundation(A2023109 to Shicheng Fan,China)。
文摘Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has spread worldwide.Effective treatments against COVID-19 remain urgently in need although vaccination significantly reduces the incidence,hospitalization,and mortality.At present,antiviral drugs including Nirmatrelvir/Ritonavir(Paxlovid^(TM)),Remdesivir,and Molnupiravir have been authorized to treat COVID-19 and become more globally available.On the other hand,traditional Chinese medicine(TCM)has been used for the treatment of epidemic diseases for a long history.Currently,various TCM formulae against COVID-19 such as Qingfei Paidu decoction,Xuanfei Baidu granule,Huashi Baidu granule,Jinhua Qinggan granule,Lianhua Qingwen capsule,and Xuebijing injection have been widely used in clinical practice in China,which may cause potential herb-drug interactions(HDIs)in patients under treatment with antiviral drugs and affect the efficacy and safety of medicines.However,information on potential HDIs between the above anti-COVID-19 drugs and TCM formulae is lacking,and thus this work seeks to summarize and highlight potential HDIs between antiviral drugs and TCM formulae against COVID-19,and especially pharmacokinetic HDIs mediated by metabolizing enzymes and/or transporters.These well-characterized HDIs could provide useful information on clinical concomitant medicine use to maximize clinical outcomes and minimize adverse and toxic effects.
文摘The combination of herbs and drugs is one of the most important approaches in the prevention and treatment of diseases in the integrated traditional and Western medicine （ITWM）. While most medical practices have proved that the combination of herbs and drugs led to a clinical efficacy that was often superior to merely using only one of them; results from some studies have triggered adverse reactions to such an approach. Since few herb-drug interaction studies were carried out during treatments combining herbs and drugs, it really restricts the development of treatment and treatment theory of the combination of herbs and drugs. Given that herb-drug interactions may occur through the main pathway of cytochrome P450 enzymes and transporters; then to exhaustively study the role and impact of herbs in drug metabolism, as well as to establish a corresponding database, is of greatsignificance for guiding the rational combination of herbs and drugs. When the herb-drug interaction information platform is implemented, we would get at ease a reasonable herb-drug prescription to achieve a better outcome, reduce dosage of some expensive drugs preserving the same efficacy, or even reduce some side effects of particular drugs; which might also promote the dynamic combination of Chinese and Western medicine, and accelerate the theory development of ITWM.
基金National Natural Science Foundation of China(Grant No.81573684)National Key Technology R&D Program "New Drug Innovation" of China(Grant No.2018ZX09711001-008-003)Beijing Municipal Science and Technology Project(Grant No.Z181100002218028)
文摘In the present study, the potential inhibition behaviors of notoginseng total saponins(NS), safflower total flavonoids(SF), and their combination(CNS) towards three major isoforms of UDP-glucuronosyltransferases(UGTs) in human liver microsomes(HLMs) were investigated to study the mechanism of the synergistic effect of CNS.Etoposide, trifluoperazine and azidothymidine were selected as the probe drugs to elucidate the activities of UGT1A1, 1A4 and 2B7 by UPLC-MS/MS method, respectively.The results showed that CNS, NS and SF significantly inhibited the activities of UGT1A1, 1A4 and 2B7(P<0.05) with the IC_(50) values less than 30 mg/mL.Furthermore, the inhibitory effects of CNS towards UGT1A1, 1A4 and 2B7 were stronger than those of NS and SF(P<0.05).In conclusion, the combination of NS and SF could increase their inhibitory effects on UGT1A1, 1A4 and 2B7 activities in HLMs and might be conducive to reduce the phase II metabolism of the effective constituents in CNS.The potential herb-drug interactions of CNS based on UGT enzymes provided a useful experimental basis for its further research and development.
基金Supported by the Construction of Scientific Evidences for Herbal Medicine Formulae(No.K16251)Evaluation of Herb-Drug Interactions(No.K16252)from the Korea Institute of Oriental Medicine
文摘Objective：To assess the effects of traditional herbal formulae Sijunzi Decoction（四君子汤,Sagunja-tang,SJZD）,Siwu Decoction（四物汤,Samul-tang,SWD）,Bawu Decoction（八物汤,Palmul-tang,BWD）and Shiquan Dabu Decoction（十全大补汤,Sipjeondaebo-tang,SDD）on the activities of human cytochrome P450（CYP450）,a drug-metabolizing enzyme.Methods：Herbal formula water extracts were filtered and lyophilized after the powder extracts were dissolved in distilled water.The activities of major human CYP450isozymes（CYP3A4,CYP2C19,CYP2D6 and CYP2E1）were measured using in vitro fluorescence-based enzyme assays.The inhibitory effects of the herbal formulas on the activities of CYP450 were characterized as half maximal inhibition concentration（IC50）values.Results：All the tested herbal formulae inhibited CYP2C19activity（IC50：SJZD,83.28μg/m L;SWD,235.54μg/m L;BWD,166.82μg/m L;SDD,178.19μg/m L）;SJZD（IC50=196.46μg/m L）,SWD（IC50=333.42μg/m L）and SDD（IC50=163.42μg/m L）inhibited CYP2E1-mediated metabolism;whereas BWD exhibited comparatively weak inhibition of CYP2E1（IC50=501.78μg/m L）.None of the four herbal formulas significantly affected CYP3A4 or CYP2D6.Conclusions：These results suggest that SJZD,SWD,BWD and SDD could potentially inhibit the metabolism of co-administered synthetic drugs whose primary route of elimination is via CYP2C19.In addition,clinically relevant pharmacokinetic interactions could occur when SJZD,SWD or SDD is co-administered with drugs metabolized by CYP2E1.Our findings provide information for the safety and effective clinical use of these four classic herbal formulas.
基金Supported by the Comprehensive and Interactive Medicine InstituteNational Research Foundation of Korea(No.2012R1A2A2A02044997)
文摘Objective： To evaluate the potential pharmacokinetic interactions of the anticancer agent gefitinib （Iressae） and the oriental medications Guipi Decoction （归脾汤, GPD, Guibi-tang in Korean） and Bawu Decoction （八物汤, BWD, Palmul-tang in Korean）. Methods： Methylceliulose （MC, control）, GPD （1,200 mg/kg）, or BWD （6,000 mg/kg） was orally administered to rats either as a single dose or multiple doses prior to gefitinib administration. To examine the effects of a single dose of the herbal medicines, gefitinib （10 mg/kg） was orally administered after 5 min or 1 h of MC or the herbal medicine pretreatments. To examine the effects of the multiple doses of the herbal medicines, gefltinib （10 mg/kg） was orally administered following 7 consecutive days of the administration of MC or each herbal medicine. The plasma concentrations of gefitinib were determined with liquid chromatography-tandem mass spectrometry assay. The plasma concentration-time profiles of gefitinib were analyzed with a noncompartmental analysis. Results： Gefitinib was rapidly absorbed and showed a mono- exponential decline with an elimination half-life of 3.7-4.1 h. The pharmacokinetics of gefitinib was not affected by GPD pretreatment. However, a significantly lower maximum plasma concentration （Crux, P〈0.05） and area under the curve （P〈0.05）, and a delayed time to reach Cmax （Tmax, P〈0.01） were observed in both single- and multiple- dose BWD-pretreated rats compared with the control rats. Conclusions： BWD and not GPD might delay and interfere with gefitinib absorption. Further evaluations of the clinical significance of these findings are needed.
基金the support from the Joint Chair in Traditional Chinese Medicine Program(New South Wales Office of Science Research,The University of Sydney and University of Western Sydney,Australia)
文摘In the 21st century, the public are more informed, mainly via the Internet, about health and medical products and have become more knowledgeable about matters relating to their health conditions and well-being in curing and preventing illnesses. They often self-medicate themselves with various health products and over-the-counter （OTC） medicines apart from prescribed pharmaceutical drugs （PD）. Some of those non-prescribed products may have doubtful quality control and contain harmful additives or unchecked ingredients; thus their usefulness is in doubt. The increasing popularity world-wide of using Chinese medicines （CM） and related OTC functional products has raised concerns over their concomitant use with PD and the consequential adverse effects. In most cases the alleged causes of adverse effects are linked with herbal sources, although the authorised information on the interactions between CM-PD is not plentiful in the literature. There is an urgent need for such a data base. The future professionals in health and medical care should be knowledgeable or aware of what their patients have been taking or given. In actual practice the patients may receive both treatments intentionally or unintentionally, with or without the awareness of the practitioner. In these situations a reliable database for interactions between CM-PD will be extremely useful for consultation when treatment problems appear or during emergency situations. Their combining of medications may be involved with possible outcomes of adverse reactions or beneficial effects. Such a database will be welcomed by both practitioners of herbal medicines and orthodox medicine practitioners in the emerging trend of integrative medicine. The author has been involved in various research projects of basic and clinical aspects in mainly CM among other herbal and PD. Examples will be given largely on those related to these disciplines as illustrations in this overview.
基金supported by the Ministry of Higher Education,Malaysia(No.UKM-JJ-03-FRGS0044-2010)Universiti Kebangsaan Malaysia(No.UKM-DPP-2014-131)
文摘Objective： The combination effect of Piperbetle （PB） and 5-fluorouracil （5-FU） in enhancing the cytotoxic potential of 5-FU in inhibiting the growth of colon cancer cells was investigated. Methods： HT29 and HCT116 cells were subjected to 5-FU or PB treatment. 5-FU and PB were then combined and their effects on both cell lines were observed after 24 h of treatment. PB-5-FU interaction was elucidated by isobologram analysis. Apoptosis features of the treated cells were revealed by annexin V/PI stain. High-performance liquid chromatography （HPLC） was performed to exclude any possible chemical interaction between the compounds. Results： In the presence of PB extract, the cytotoxicity of 5-FU was observed at a lower dose （IC^0 12.5 pmol/L） and a shorter time （24 h） in both cell lines. Both cell lines treated with 5-FU or PB alone induced a greater apoptosis effect compared with the combination treatment. Isobologram analysis indicated that PB and 5-FU interacted synergistically and antagonistically in inhibiting the growth of HT29 and HCT116 cells, respectively. Conclusions： In the presence of PB, a lower dosage of 5-FU is required to achieve the maximum drug effect in inhibiting the growth of HT29 cells. However, PB did not significantly reduce 5-FU dosage in HCT116 cells. Our result showed that this interaction may not solely contribute to the apoptosis pathway.
文摘Objectives: Radix Polygoni Multiflori Praeparata (RPMP) and Dioscorea Bulbifera Rhizomes (DBR) are used in Chinese herbal medicine and have been frequently reported for adverse reactions on liver. In this research, we aimed to evaluate in vivo effects of RPMP and DBR on rat cytochrome P450 enzymes (CYP1A2, CYP2E1 and CYP3A2) with their respective substrates as probes. Methods: Rats were orally administered RPMP, DBR and RPMP/DBR combination at 12, 10 and (12 + 10) g/kg, respectively, or saline as a control, once daily for 7 days. Thereafter, a cocktail containing 10 mg/kg caffeine, 20 mg/kg chlorzoxazone and 10 mg/kg dapsone was tail vein injected to rats. At defined time points, plasma drug concentrations were simultaneously evaluated by HPLC. Pharmacokinetic parameters simulated by DAS software were used to assess RPMP and/or DBR effects on cytochrome P450 enzymes activity. ANOVA and Dunnett’s test were used for data analysis. Results: Caffeine metabolism was enhanced in RPMP animals and reduced after pretreatment with DBR, but no effect was observed in RPMP/DBR combination group. Chlorzoxazone and dapsone metabolism was enhanced in both RPMP and DBR groups and consequently in combination group. The data suggested that RPMP independently induces rat CYP1A2, CYP2E1 and CYP3A2 activity, while DBR independently inhibits activity of rat CYP1A2 and induces that of CYP2E1 and CYP3A2. RPMP/DBR combination showed no significant benefit compared with the two drugs alone and even showed a neutralized effect in CYP1A2 activity. Conclusions: Caution is needed when RPMP and/or DBR are co-administered with drugs metabolized by human CYP1A2, CYP2E1 and CYP3A4.
基金This work was supported by the USA National Center for Com-plementary and Integrative Health Grant R21AT011088(to X.Ma)in part by Grant U54AT008909(to M.F.Paine)+1 种基金in part by the USA National Institute of Allergy and Infectious Diseases Grant R01AI131983(to X.Ma)National Institute of Diabetes and Digestive and Kidney Diseases Grant R01DK126875(to X.Ma).
文摘Background and aims:The herbal supplement Gancao,also known as licorice,belongs to the genus Glycyrrhiza and has been used worldwide for its hepatoprotective effect.Recent studies have raised concerns about potential herb-drug interactions associated with Gancao via pregnane X receptor(PXR)-mediated induction of hepatic cytochrome P4503A4(CYP3A4).The current work aimed to determine the phytochemicals in Gancao that activate PXR and induce CYP3A4.Methods:DPX2 cells were used for cell-based PXR reporter assays.The phytochemicals in Gancao extract were identified using a metabolomics approach.The effects of PXR activators identified from in vitro studies were further investigated in PXR-and CYP3A4-humanized mouse models.Results:Gancao was verified to be a PXR-activating herb.Two major phytochemicals in Gancao,gly-cyrrhizin(GZ)and glycyrrhetinic acid(GA),did not activate PXR in the cell-based reporter assays.However,glabridin was shown to activate PXR in a dose-dependent manner.In vivo studies confirmed that GZ is not a PXR activator and glabridin is a weak PXR activator.Although GA did not active PXR in vitro,it induced CYP3A4 expression in a PXR-dependent manner in the PXR-and CYP3A4-humanized mice.
文摘Angelica dahurica is commonly referred to as ‘Baizhi’ in China and has been noted for its therapeutic significance. The major active ingredients of Angelica dahurica is coumarin, which is reported as a kind of potent inhibitor of cytochrome P450 enzymes (CYP450s). The aim of this study was to investigate the inhibition of CYP3A enzymes by total coumarin extract (TCE) obtained from dried root of Angelica dahurica by using in situ single pass intestinal perfusion (SPIP) and in situ liver perfusion in rats. When midazolam (MDZ) which is a substrate of CYP3A co-perfused with TCE (198 μg/mL) from Baizhi in duodenum and ileum segments, the Peff of MDZ has increased significantly compared with the MDZ single perfused group (p 0.05) (n = 6). During in situ liver perfusion study, the results demonstrated that, 3 days oral administration of TCE obtained from Baizhi could significantly reduce the elimination rate of MDZ in the perfusate (p Angelica dahurica extract co-administrated with drugs which are the substrates of CYP3A, much more attention should be paid rather than that of other CYP450 enzymes. These findings may facilitate in predicting possible herb-drug interactions (HDIs) when Angelica dahurica is used in combination with other drugs, and decrease the incidence of the CYP450-mediated HDIs.
基金BSDT’s Ayurvedic College, Synapse Laboratory Pvt. Ltd., National Toxicology Center, & National Centre for Cell Science, Pune for extending their kind support to carry out this work
文摘OBJECTIVE： Consuming botanical dietary supplements or herbal drugs along with prescription drugs may lead to potential pharmacokinetic-pharmacodynamic（PK-PD） herb-drug interactions（HDI）. The present study focuses on the importance of and novel approach for assessing HDI in integrative medicine with case examples of two frequently-used Ayurvedic Rasayana botanicals.METHODS： The aqueous extracts of Asparagus racemosus（ARE） and Gymnema sylvester（GSE） were prepared as per Ayurvedic Pharmacopoeia of India. Chemoprofiling of these extracts was done using high-performance liquid chromatography（HPLC）. Additionally, ARE was characterized for the presence of shatavarins IV and I using HPLC ＆ mass spectroscopy respectively. Effects of ARE and GSE were investigated on rat liver microsome using testosterone probe drug assay. The changes in formation of metabolite（6-β hydroxy testosterone） were monitored on incubation of testosterone alone, testosterone with ketoconazole, ARE and GSE using HPLC. Half inhibitory concentration（IC50） was used to predict plausible HDI.RESULTS： ARE and GSE showed no inhibition with IC50 values 〉1 000 μg/m L while the standard inhibitor ketoconazole completely abolished CYP3A4-dependent activity at 0.531 μg/m L and IC50 was found to be 0.036 μg/m L.CONCLUSION： ARE and GSE prepared as per Ayurvedic Pharmacopoeia of India were found to be safe for CYP3A4-mediated inhibitory HDI in rats. Our in vitro study suggests the need of further in vivo investigation for HDI in order to provide clinical relevance.
文摘The present study was intended to discover the interaction between Ocimum sanctum(O. sanctum) and Glimepiride, a sulfonylurea derivative used in the treatment of type-2 diabetes, in diabetic rats to suggest an alteration in the dose of Glimepiride in case of hypoglycaemia. LD50 studies for the aqueous extract of O. sanctum leaf were carried out in albino mice up to the dose level of 2000 mg/kg. O. sanctum at low, medium and high doses(100, 200 and 400 mg/kg, per oral), respectively and Glimepiride ?(half) therapeutic dose, therapeutic dose and 2 time therapeutic dose(0.036, 0.072 and 0.144 mg/200 g, per oral) were selected. After the treatment with O. sanctum and Glimepiride as single doses and in various combinations of these two drugs in streptozotocin-induced diabetic rats serum glucose levels in all the groups were analysed by the glucose oxidase-peroxidase method. When administered alone as single doses both aqueous extract of O. sanctum leaf and Glimepiride produced a significant anti-diabetic effect in diabetic rats. The anti-diabetic effect observed with combination of aqueous extract of O. sanctum leaf and Glimepiride was significant and more when compared to either of the drugs given alone. There was a definite interaction that necessitates dose readjustment of Glimepiride and further glucose levels are to be frequently monitored to avoid complication of hypoglycemic condition with aqueous extract of O. sanctum leaf and Glimepiride combination.
文摘BACKGROUND： P-glycoprotein （P-gp） is a 170-kDa membrane protein. It provides a barrier function and help to excrete toxins from the body as a transporter. Some bioflavonoids have been shown to block P-gp activity. OBJECTIVE： To evaluate the important amino acid residues within nucleotide binding domain 1 （NBD l） of P-gp that play a key role in molecular interactions with flavonoids using structure-based pharmacophore model. METHODS： In the molecular docking with NBD 1 models, a putative binding site of flavonoids was proposed and compared with the site for ATP. The binding modes for ligands were achieved using LigandScout to generate the P-gp-flavonoid pharmacophore models. RESULTS： The binding pocket for flavonoids was investigated and found these inhibitors compete with the ATP for binding site in NBD1 including the NBD1 amino acid residues identified by the in silico techniques to be involved in the hydrogen bonding and van der Waals （hydrophobic） interactions with flavonoids. CONCLUSION： These flavonoids occupy with the same binding site of ATP in NBD1 proffering that they may act as an ATP competitive inhibitor.
基金the Construction of Scientific Evidences for Herbal Medicine Formulas(K16251) and Evaluation of Herb-Drug Interactions(No.K16252) grant from the Korea Institute of Oriental Medicine(KIOM)
文摘OBJECTIVE:To investigate the influence of Yin-tonification herbal formulas Jaeumganghwa-tang(Ziyin Jianghuo Tang,JEGHT),Ssanghwa-tang(Shuanghe Tang,SHT) and Yukmijihwang-tang(Liuwei Di huang Tang,YMJHT) on the activities of human major cytochrome P450(CYP450 s) and UDP-glucuronosyltransferases isozymes(UGTs) in vitro.METHODS:The activities of CYP450 s(CYP1 A2,CYP3 A4,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6 and CYP2 E1) and UGTs(UGT1 A1,UGT1 A4 and UGT2 B7)were assessed using in vitro fluorescence-and luminescence-based enzyme assays,respectively.The effects of herbal formulas on the activities of CYP450 s and UGTs were presented as IC50 values.RESULTS:JEGHT showed the potent inhibition of the CYP2 D6 activity,with weak inhibition on the activities of CYP1 A2,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 E1,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7.SHT inhibited the activities of CYP1 A2 and CYP2 E1,whereas the negligible inhibition of the activities of CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7 through SHT was observed.YMJHT inhibited CYP2 E1 activity,with a negligible inhibition on the activities of CYP1 A2,CYP2 B6,CYP2 C9,CYP2 C19,CYP2 D6,CYP3 A4,UGT1 A1,UGT1 A4 and UGT2 B7.CONCLUSION:These findings provide information about the potential interactions between three Yin-tonification herbal formulas and conventional drugs.
