Herb-drug interaction in the protective effect of Alpinia officinarum against gastric injury induced by indomethacin based on pharmacokinetic, tissue distribution and excretion studies in rats

Alpinia officinarum Hance of the Chinese traditional herb for the treatment of emesis, abdominal pain and diarrhea has been used to counteract gastric disease induced by indomethacin in rats without obvious side effects. However, the role of herb-drug interaction between indomethacin and A. officinarum based on pharmacokinetic, tissue distribution and excretion still remains unknown. In this study, an ultra-fast liquid-tandem mass spectrometry(UFLC-MS/MS) method was developed for simultaneous determination of indomethacin and its three metabolites, O-desmethylindomethacin(ODI), deschlorobenzoylindomethacin(NDI) and indomethacin acyl-b-D-glucuronide(IDAbG) by oral administration of indomethacin solution with and without the ethanolic extract of A. officinarum and applied to comparative pharmacokinetic, tissue distribution and excretion studies. Our results clarified that oral administration of A. officinarum produced significant alterations in the pharmacokinetic parameters of indomethacin. And the pharmacokinetic interaction between indomethacin and A. officinarum reduced the systemic exposure of indomethacin and increased its elimination. Tissue distribution results demonstrated that co-administration of A. Officinarum could not reduce the accumulation of indomethacin in the target tissue of the stomach, but could accelerate the excretions of indomethacin and its three metabolites including ODI, NDI and IDAb G in the bile and feces of rats in the excretion study.Therefore, A. Officinarum might have a gastrointestinal protective effect through the interaction role with indomethacin based on the pharmacokinetics and excretion in rats.

Carboxylesterases mediated herb-drug interactions:a systematic review

Esterases participate in the metabolism of^10%of the clinical drugs that contain ester or amide bonds,but the esterases mediated drug/herb-drug interactions(DDIs or HDIs)have not been reviewed in depth.Carboxylesterases(CEs),the most abundant esterases expressed in the metabolic organ of mammals,play a pivotal role in hydrolysis of a variety of endogenous and xenobiotic esters.In the human body,two predominant carboxylesterases including hCE1 and hCE2 have been identified and extensively studied over the past decade.These two enzymes have been found with hydrolytic activity towards a variety of endogenous esters and ester-containing drugs.Recent studies have demonstrated that strong inhibition on hCEs may slow down the hydrolysis of CEs substrates,which may affect their pharmacokinetic properties and thus trigger potential DDIs or HDIs.Over the past decade,many herbal extracts and herbal constitutes have been found with strong inhibitory effects against CEs,and their potential risks on herb-drug interactions(HDIs)have also attracted much attention.This review focused on recent progress in hCEs mediated herb-drug interactions.The roles of hCEs in drug metabolism,the inhibitory capacities and inhibition mechanism of a variety of herbal extract and herbal constitutes against hCEs have been well summarized.Furthermore,the challenges and future perspectives in this field are highlighted by the authors.All information and knowledge presented in this review will be very helpful for the pharmacologists to deeper understand the metabolic interactions between herbal constituents and hCEs,as well as for clinical clinicians to reasonable use herbal medicines for alleviating hCEs-associated drug toxicity or avoiding the occurrence of clinically relevant hCEs-mediated HDIs.

Potential Mechanism of Herb-Drug Interaction Mediated by Angelica dahurica: Inhibition on CYP3A Enzymes in Rats

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.

Antibacterial activity of Rosmarinus officinalis L.alone and in combination with cefuroxime against methicillin-resistant Staphylococcus aureus

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.

Empathizing with Emotional Robot Based on Cognition Reappraisal

This paper proposes a continuous cognitive emotional regulation model for robot in the case of external emotional stimulus from interactive person's expressions. It integrates a guiding cognitive reappraisal strategy into the HMM(Hidden Markov Model) emotional interactive model for empathizing between robot and person. The emotion is considered as a source in the 3D space(Arousal, Valence, and Stance). State transition and emotion intensity can be quantitatively analyzed in the continuous space. This cognition-emotion interactive model have been verified by the expression and behavior robot. Empathizing is the main distinguishing feature of our work, and it is realized by the emotional regulation which operated in a continuous 3D emotional space enabling a wide range of intermediate emotions. The experiment results provide evidence with acceptability, accuracy, richness, fluency, interestingness, friendliness and exaggeration that the robot with cognition and emotional control ability could be better accepted in the human-robot interaction(HRI).

The consistent Riccati expansion and new interaction solution for a Boussinesq-type coupled system

Starting from the Davey-Stewartson equation, a Boussinesq-type coupled equation system is obtained by using a variable separation approach. For the Boussinesq-type coupled equation system, its consistent Riccati expansion （CRE） solvability is studied with the help of a Riccati equation. It is significant that the soliton--cnoidal wave interaction solution, expressed explicitly by Jacobi elliptic functions and the third type of incomplete elliptic integral, of the system is also given.

Creep-Fatigue Interaction Life Consumption of Industrial Gas Turbine Blades

This paper presents the creep-fatigue interaction life consumption of industrial gas turbine blades using the LM2500+ engine operated at Pulrose Power station, Isle of Mann as a case study. The linear damage summation approach where creep damage and fatigue damage are combined was used for the creep-fatigue interaction life consumption of the target blades. The creep damage was modelled with the Larson-Miller parameter method while fatigue damage was assessed with the modified universal slopes method and the damage due to creep-fatigue interaction was obtained from the respective life fractions. Because of the difficulty in predicting the life of engine components accurately, relative life consumption analysis was carried out in the work using the concept of creep-fatigue interaction factor which is the ratio of the creep-fatigue interaction life obtained from any condition of engine operation to a reference creep-fatigue interaction life. The developed creep-fatigue interaction life consumption analysis procedure was applied to 8 most of real engine operation. It was observed that the contribution of creep to creep-fatigue interaction life consumption is greater than that of fatigue at all ambient temperatures. The fatigue contribution is greater at lower ambient temperatures as against higher ambient temperatures. For the case study, the overall equivalent creep-fatigue factor obtained was 1.5 which indicates safe engine operation compared to the reference condition. The developed life analysis algorithm could be applied to other engines and could serve as useful tool in engine life monitoring by engine operators.

Potential herb-drug interactions between anti-COVID-19 drugs and traditional Chinese medicine

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.

Adsorption behavior of iron phthalocyanine on a Ag(110) surface

An investigation on the growth behavior of FePc on a Ag （110） surface is carried out by using scanning tunneling microscopy （STM）. At an FePc coverage of 3.5 ML, an ordered superstructure （densely packed） with a lateral shift is observed. The densely packed superstructure can be attributed to the substrate commensuration and the intermolecular van der Waals attractive interaction. The in-plane lateral shift in the superphase is specifically along the direction of [110] azimuth. The results provide a new perspective to understanding the intermolecular and the molecule-substrate interactions.

Multi Multi-Cell Uplink Interference Management Cell Uplink Interference Management: A Distributed Power Control Method

This paper investigates a multi-cell uplink network,where the orthogonal frequency division multiplexing(OFDM)protocol is considered to mitigate the intra-cell interference.An optimization problem is formulated to maximize the user sup-porting ratio for the uplink multi-cell system by optimizing the transmit power.This paper adopts the user supporting ratio as the main performance metric.Our goal is to improve the user supporting ratio of each cell.Since the formulated optimization problem is non-convex,it cannot be solved by using traditional convex-based optimi-zation methods.Thus,a distributed method with low complexity and a small amount of multi-cell interaction is proposed.Numerical results show that a notable perfor-mance gain achieved by our proposed scheme compared with the traditional one is without inter-cell interaction.

Radix Polygoni Multiflori Praeparata and Dioscorea Bulbifera Rhizome Decoctions Display Combined Effects Detected by a Three-Probe Drug Cocktail with Substrates of Rat Hepatic Cytochrome P450 Enzymes

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.

Herb-drug Interaction:An Emerging Issue of Integrative Medicine

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,

Potential Herb-Drug Interaction in the Prevention of Cardiovascular Diseases during Integrated Traditional and Western Medicine Treatment

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.

Herb-drug enzyme-mediated interactions and the associated experimental methods： a review

OBJECTIVE: To review the interactions between herbs and widely used drugs and summarize the associated experimental methods.METHODS: Definite herb-drug interactions were obtained by searching Pub Med, other large overseas databases and summarizing new researches from China. We summarize some methods to assess the interaction between herbs and drugs involving microsomal, cell culture and animal experiments, and clinical trials, classifying this method as single ingredient herbs, crude herb extracts, andherbal formulae.RESULTS: Many herbs interact with drugs through a complex cytochrome P450 and/or P-glycoprotein mechanism. Herb-induced enzyme inhibition and/or induction may result in enhanced and / or decreased plasma, tissue, urine and bile drug concentrations, leading to a change in a drug's pharmacokinetic parameters and resulting in the improper treatment of patients and potentially severe side effects. Use of an appropriate method for comprehensively assessing herb-drug interactions can minimize clinical risks. Different methods were used by researchers to assess the pharmacological changes of drugs in vivo and in vitro and the mechanisms of the interactions from microsomal, cell culture and animal experiments, and clinical trials are discussed in this review.CONCLUSION: Co-medication with herbs can result in changes in pharmacological effects of many drugs. This review describes the assessment of single-ingredient herbs, crude herb extracts, and herbal formulae. When choosing a research method to investigate herb-drug interactions, the properties of the drugs and herbs should be considered.

Activation of PXR causes drug interactions with Paxlovid in transgenic mice

Paxlovid is a nirmatrelvir(NMV)and ritonavir(RTV)co-packaged medication used for the treatment of coronavirus disease 2019(COVID-19).The active component of Paxlovid is NMV and RTV is a pharmacokinetic booster.Our work aimed to investigate the drug/herb-drug interactions associated with Paxlovid and provide mechanism-based guidance for the clinical use of Paxlovid.By using recombinant human cytochrome P450s(CYPs),we confirmed that CYP3A4 and 3A5 are the major enzymes responsible for NMV metabolism.The role of CYP3A in Paxlovid metabolism were further verified in Cyp3a-null mice,which showed that the deficiency of CYP3A significantly suppressed the metabolism of NMV and RTV.Pregnane X receptor(PXR)is a ligand-dependent transcription factor that upregulates CYP3A4/5 expression.We next explored the impact of drug-and herb-mediated PXR activation on Paxlovid metabolism in a transgenic mouse model expressing human PXR and CYP3A4/5.We found that PXR activation increased CYP3A4/5 expression,accelerated NMV metabolism,and reduced the systemic exposure of NMV.In summary,our work demonstrated that PXR activation can cause drug interactions with Paxlovid,suggesting that PXR-activating drugs and herbs should be used cautiously in COVID-19 patients receiving Paxlovid.

Effects of Rong Shuan capsule, Xue Zhi Kang capsule, Xin Yuan capsule and Songling Xue Mai Kang capsule on the pharmacokinetics of clopidogrel active metabolite in rats

In the present study, we aimed to examine the effects of Rong Shuan capsule, Xue Zhi Kang capsule, Xin Yuan capsule and Songling Xue Mai Kang capsule on the pharmacokinetics of clopidogrel active metabolite（CAM）. The traditional Chinese medicines（TCMs） Rong Shuan capsule, Xue Zhi Kang capsule, Xin Yuan capsule and Songling Xue Mai Kang capsule are widely used to treat cardiovascular disease in China. They are often prescribed in combination with clopidogrel, a common anti-platelet Western drug. We investigated the influence of the four TCMs on CAM pharmacokinetics following administration at human dose in rats. Pharmacokinetic parameters were determined following oral（PO） administration of clopidogrel（7.5 mg/kg） with or without Rong Shuan capsule（75 mg/kg, PO）, Xue Zhi Kang capsule（60 mg/kg, PO）, Xin Yuan capsule（120 mg/kg, PO）, or Songling Xue Mai Kang capsule（150 mg/kg, PO）. Compared with the animals in the control group, Xue Zhi Kang capsule significantly decreased the area under the plasma concentration-time curve（AUC_（0-t）） of the CAM derivative by 25.4%. However, the t1/2 and Vz/F of CAM derivative were significantly increased by 43.6% and 70.7%, respectively. It was also observed that the pharmacokinetic parameters were altered in groups pretreated with Rong shuan capsule, Xin yuan capsule or Songling Xue mai kang capsule compared with the control group, but not significant. This study indicated that Xue Zhi Kang capsule had an effect on the formation and metabolism of CAM. Therefore, in the beginning of co-administration of Xue Zhi Kang capsule and clopidogrel, the anti-platelet efficacy might be compromised because of the decreased formation of CAM. Otherwise, long-time co-administration might lead to side effects by the prolongation of the t1/2 and Vz/F increase of CAM.

Inhibitory effect of the combination of notoginseng total saponins and safflower total flavonoids on UDP-glucuronosyltransferases 1A1, 1A4, and 2B7 in human liver microsomes

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.

High degree of pharmacokinetic compatibility exists between the five-herb medicine XueBiJing and antibiotics comedicated in sepsis care

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.

Isochlorogenic acid A affects P450 and UGT enzymes in vitro and in vivo

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.

Multi-origin alkanes related to CO_2-rich, mantle-derived fluid in Dongying Sag, Bohai Bay Basin

With the newly obtained carbon isotope data for the natural gas, a pilot study of multiple-sourced alkanes related to the mantled-derived fluid is presented. The carbon isotope values of alkanes in the Dongying Sag possess the features indicating a general organic origin. However, there are two sub-populations in the isotopic data set, which reflect two specific types of origins. In general, the sub-population with high δ13CCH4 values is related to the CO2-rich, mantle-derived fluid, and it is distributed in the belts where mantle-derived fluid flow and basic volcanic activities have occurred. Geological and geochemical studies demonstrate that this variation of methane carbon isotope values in the Dongying Sag is unrelated with the basin bury and thermal histories, types of source rocks, and reactions between basin fluid and rocks. Mixing of mantle-derived fluid and organic sourced hydrocarbons is probably the cause for the variation.