The role of microbial partners in heavy metal metabolism in plants: a review.

Heavy metal pollution threatens plant growth and development as well as ecological stability. Here, we synthesize current research on the interplay between plants and their microbial symbionts under heavy metal stress, highlighting the mechanisms employed by microbes to enhance plant tolerance and resilience. Several key strategies such as bioavailability alteration, chelation, detoxification, induced systemic tolerance, horizontal gene transfer, and methylation and demethylation, are examined, alongside the genetic and molecular basis governing these plant-microbe interactions. However, the complexity of plant-microbe interactions, coupled with our limited understanding of the associated mechanisms, presents challenges in their practical application. Thus, this review underscores the necessity of a more detailed understanding of how plants and microbes interact and the importance of using a combined approach from different scientific fields to maximize the benefits of these microbial processes. By advancing our knowledge of plant-microbe synergies in the metabolism of heavy metals, we can develop more effective bioremediation strategies to combat the contamination of soil by heavy metals.

The Molecular Genetics and Genomics of Plant-Pathogen Interactions.

Plants have evolved an intricate immune system to protect themselves from potential pathogens [...].

Evaluation of drug interactions of Saposhnikoviae Radix and its major components with astragaloside IV and paeoniflorin using in vitro and in vivo experiments.

Saposhnikoviae Radix (SR) may enhance the pharmacodynamics of Huangqi Chifeng Tang (HQCFT) in the treatment of cerebral infarction according to our previous research, but the underlying mechanism is unknown. Herein, an in vivo pharmacokinetic assay in rats and in vitro MDCK-MDR1 cell assays were used to investigate the possible mechanism of SR, its main components, and its interactions with Astragali Radix (AR) and Paeoniae Radix (PR). An ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC‒MS/MS)-based analytical method for quantifying astragaloside IV (ASIV) and paeoniflorin (PAE) in microdialysis and transport samples was developed. The pharmacokinetic parameters of SR were determined using noncompartmental analyses CCK-8 assays were used to detect the cytotoxicity of ASIV, PAE, cimifugin (CIM), prim-o-glucosylcimifugin (POG) and their combinations. Moreover, drug transport was studied using MDCK-MDR1 cells. Western blotting was performed to measure the protein expression levels of P-GP and MRP1. Claudin-5, ZO-1, and F-actin expression was determined via immunohistochemical staining of MDCK-MDR1 cells. harmacokinetic studies revealed that, compared with those of Huangqi Chifeng Tang-Saposhnikoviae Radix (HQCFT-SR), the Tmax of ASIV increased by 11.11 %, and the MRT0-t and Tmax of PAE increased by 11.19 % and 20 %, respectively, in the HQCFT group. Transport studies revealed that when ASIV was coincubated with 28 µM CIM or POG, the apparent permeability coefficient (Papp) increased by 71.52 % and 50.33 %, respectively. Coincubation of PAE with 120 µM CIM or POG increased the Papp by 87.62 % and 60.95 %, respectively. Moreover, CIM and POG significantly downregulated P-gp and MRP1 (P < 0.05), inhibited the expression of Claudin-5, ZO-1, and F-actin (P < 0.05), and affected intercellular tight junctions (TJs). In conclusion, our study successfully established a selective, sensitive and reproducible UPLC‒MS/MS analytical method to detect drug‒drug interactions between SR, AR and PR in vivo and in vitro, which is beneficial for enhancing the therapeutic efficacies of AR and PR. Moreover, this study provides a theoretical basis for further research on the use of SR as a drug carrier.

Use of herbal medication in the perioperative period: Potential adverse drug interactions.

Use of herbal medications and supplements has experienced immense growth over the last two decades, with retail sales in the USA exceeding $13 billion in 2021. Since the Dietary Supplement Health and Education Act (DSHEA) of 1994 reduced FDA oversight, these products have become less regulated. Data from 2012 shows 18% of U.S. adults used non-vitamin, non-mineral natural products. Prevalence varies regionally, with higher use in Western states. Among preoperative patients, the most commonly used herbal medications included garlic, ginseng, ginkgo, St. John's wort, and echinacea. However, 50-70% of surgical patients fail to disclose their use of herbal medications to their physicians, and most fail to discontinue them preoperatively. Since herbal medications can interact with anesthetic medications administered during surgery, the American Society of Anesthesiologists (ASA) and the American Association of Nurse Anesthetists (AANA) recommend stopping herbal medications 1-2 weeks before elective surgical procedures. Potential adverse drug effects related to preoperative use of herbal medications involve the coagulation system (e.g., increasing the risk of perioperative bleeding), the cardiovascular system (e.g., arrhythmias, hypotension, hypertension), the central nervous system (e.g., sedation, confusion, seizures), pulmonary (e.g., coughing, bronchospasm), renal (e.g., diuresis) and endocrine-metabolic (e.g., hepatic dysfunction, altered metabolism of anesthetic drugs). During the preoperative evaluation, anesthesiologists should inquire about the use of herbal medications to anticipate potential adverse drug interactions during the perioperative period.

Herb-drug interactions: Quantitative analysis of levofloxacin absorption and transporter expression in the rat intestine following combined treatment with Persicaria capitata (Buch.-Ham. ex D. Don) H. Gross.

Persicaria capitata (Buch.-Ham. ex D. Don) H. Gross, a traditional Chinese medicinal plant, is often used to treat various urologic disorders in China. P. capitata extracts (PCE) have been used in combination with levofloxacin (LVFX) to treat urinary tract infections (UTIs) for a long time. However, little is known about the absorption of LVFX and transporter expression in the intestine after combined treatment with PCE, restricting the development and utilization of PCE. In view of this, a UPLC-MS/MS method was established for the determination of LVFX in intestinal sac fluid samples and in situ intestinal circulation perfusate samples to explore the effect of PCE on the intestinal absorption characteristics of LVFX ex vivo and in vivo. To further evaluate the interaction between LVFX and PCE, western blotting, immunohistochemistry, and RT-qPCR were utilized to determine the expression levels of drug transporters (OATP1A2, P-gp, BCRP, and MRP2) involved in the intestinal absorption of LVFX after combined treatment with PCE. Using the everted intestinal sac model, the absorption rate constant (Ka) and cumulative drug absorption (Q) of LVFX in each intestinal segment were significantly lower in groups treated with PCE than in the control group. Ka at 2 h decreased most in the colon segment (from 0.088 to 0.016 µg/h·cm2), and Q at 2 h decreased most in the duodenum (from 213.29 to 33.92 µg). Using the intestinal circulation perfusion model, the Ka value and percentage absorption rate (A) of LVFX in the small intestine decreased significantly when PCE and LVFX were used in combination. These results showed that PCE had a strong inhibitory effect on the absorption of LVFX in the rat small intestine (ex vivo and in vivo intestinal segments). In addition, PCE increased the protein and mRNA expression levels of efflux transporters (P-gp, BCRP, and MRP2) and decreased the expression of the uptake transporter OATP1A2 significantly. The effects increased as the PCE concentration increased. These findings indicated that PCE changed the absorption characteristics of levofloxacin, possibly by affecting the expression of transporters in the small intestine. In addition to revealing a herb-drug interaction (HDI) between PCE and LVFX, these results provide a basis for further studies of their clinical efficacy and mechanism of action.

Pharmacokinetic analysis of antiviral drug ritonavir across the blood-brain barrier and its interaction with Scutellaria baicalensis using multisite microdialysis in rats.

Ritonavir, an excellent inhibitor of CYP3A4, has recently been combined with nirmatrelvir to form Paxlovid for the treatment of severe acute respiratory syndrome coronavirus 2 infections. The root of Scutellaria baicalensis Georgi (S. baicalensis), a traditional Chinese medicinal (TCM) herb commonly used to treat heat/inflammation in the lung and digestive tracts, which are major organs targeted by viral infections, contains flavones that can influence the CYP3A metabolism pathway. To investigate the ability of ritonavir to cross the bloodbrain barrier (BBB) and its potential herb-drug interactions with an equivalent TCM clinical dose of S. baicalensis, multisite microdialysis coupled with an LCMS/MS system was developed using rat model. Pretreatment with S. baicalensis extract for 5 days, which contains less flavones than those used in previous studies, had a significant influence on ritonavir, resulting in a 2-fold increase in the total concentration of flavones in the blood and brain. Treatment also boosted the maximum blood concentration of flavones by 1.5-fold and the maximum brain concentration of flavones by 2-fold, all the while exerting no noticeable influence on the transfer ratio across the bloodbrain barrier. These experimental results demonstrated that the use of a typical traditional Chinese medicinal dose of S. baicalensis is sufficient to influence the metabolic pathway and synergistically increase the concentration of ritonavir in rats.

Investigation of the drug-drug interaction and incompatibility mechanism between Aconitum carmichaelii Debx and Pinellia ternata (Thunb.) Breit.

ETHNOPHARMACOLOGICAL RELEVANCE: The combination of Aconitum carmichaelii Debx (Chuanwu, CW) and Pinellia ternata (Thunb.) Breit (Banxia, BX) forms an herbal pair within the eighteen incompatible medicaments (EIM), indicating that BX and CW are incompatible. However, the scientific understanding of this incompatibility mechanism, especially the corresponding drug-drug interaction (DDI), remains complex and unclear. AIM OF THE STUDY: This study aims to explain the DDI and potential incompatibility mechanism between CW and BX based on pharmacokinetics and cocktail approach. MATERIALS AND METHODS: Ultraperformance liquid chromatography-tandem mass spectrometry methods were established for pharmacokinetics and cocktail studies. To explore the DDI between BX and CW, in the pharmacokinetics study, 10 compounds were determined in rat plasma after administering CW and BX-CW herbal pair extracts. In the cocktail assay, the pharmacokinetic parameters of five probe substrates were utilized to assess the influence of BX on cytochrome P450 (CYP) isoenzyme (dapsone for CYP3A4, phenacetin for CYP1A2, dextromethorphan for CYP2D6, tolbutamide for CYP2C9, and omeprazole for CYP2C19). Finally, the DDI and incompatibility mechanism of CW and BX were integrated to explain the rationality of EIM theory. RESULTS: BX not only enhances the absorption of aconitine and benzoylaconine but also accelerates the metabolism of mesaconitine, benzoylmesaconine, songorine, and fuziline. Moreover, BX affects the activity of CYP enzymes, which regulate the metabolism of toxic compounds. CONCLUSIONS: BX altered the activity of CYP enzymes, consequently affecting the metabolism of toxic compounds from CW. This incompatibility mechanism may be related to the increased absorption of these toxic compounds in vivo.

Intensive pasture management alters the composition and structure of plant-pollinator interactions in Sibiu, Romania.

Background: Land management change towards intensive grazing has been shown to alter plant and pollinator communities and the structure of plant-pollinator interactions in different ways across the world. Land-use intensification in Eastern Europe is shifting highly diverse, traditionally managed hay meadows towards intensive pastures, but few studies have examined how this influences plant-pollinator networks. We hypothesized that the effects of intensive grazing on networks will depend on how plant communities and their floral traits change. Methods: We investigated plant and pollinator diversity and composition and the structure of plant-pollinator interactions near Sibiu, Romania at sites that were traditionally managed as hay meadows or intensive pastures. We quantified the identity and abundance of flowering plants, and used transect walks to observe pollinator genera interacting with flowering plant species. We evaluated the effects of management on diversity, composition and several indices of network structure. Results: Pollinator but not plant diversity declined in pastures and both plant and pollinator taxonomic composition shifted. Functional diversity and composition remained unchanged, with rather specialized flowers having been found to dominate in both hay meadows and pastures. Apis mellifera was found to be the most abundant pollinator. Its foraging preferences played a crucial role in shaping plant-pollinator network structure. Apis mellifera thus preferred the highly abundant Dorycnium herbaceum in hay meadows, leading to hay meadows networks with lower Shannon diversity and interaction evenness. In pastures, however, it preferred less abundant and more generalized flower resources. With pollinators being overall less abundant and more generalized in pastures, we found that niche overlap between plants was higher. Discussion: With both hay meadows and pastures being dominated by plant species with similar floral traits, shifts in pollinator preferences seem to have driven the observed changes in plant-pollinator interaction networks. We thus conclude that the effects of grazing on pollinators and their interactions are likely to depend on the traits of plant species present in different management types as well as on the effects of grazing on plant community composition. We thereby highlight the need for better understanding how floral abundance shapes pollinator visitation rates and how floral traits may influence this relationship.

An acute herb-drug interaction of Magnoliae Officinalis Cortex with methotrexate via inhibiting multidrug resistance-associated protein 2.

Magnoliae Officinalis Cortex (MOC), an herbal drug, contains polyphenolic lignans mainly magnolol (MN) and honokiol (HK). Methotrexate (MTX), a critical drug for cancers and autoimmune deseases, is a substrate of multidrug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). This study investigated the effect of coadministration of MOC on the pharmacokinetics of MTX and relevant mechanisms. Sprague-Dawley rats were orally administered MTX alone and with single dose (2.0 and 4.0 g/kg) and repeated seven doses of MOC (2.0 g/kg thrice daily for 2 days, the 7th dose given at 0.5 h before MTX). The serum concentrations of MTX were determined by a fluorescence polarization immunoassay. The results showed that a single dose of MOC at 2.0 g/kg significantly increased the AUC0-t and MRT of MTX by 352% and 308%, and a single dose at 4.0 g/kg significantly enhanced the AUC0-t and MRT by 362% and 291%, respectively. Likewise, repeated seven doses of MOC at 2.0 g/kg significantly increased the AUC0-t and MRT of MTX by 461% and 334%, respectively. Mechanism studies indicated that the function of MRP2 was significantly inhibited by MN, HK and the serum metabolites of MOC (MOCM), whereas BCRP was not inhibited by MOCM. In conclusion, coadministration of MOC markedly enhanced the systemic exposure and mean residence time of MTX through inhibiting the MRP2-mediated excretion of MTX.

Black Cohosh Interactions with Prescription Medications Associated with Serotonin Toxicity and Rhabdomyolysis: A Case Report.

BACKGROUND: Serotonin toxicity is a well-described phenomenon that is commonly attributed to a variety of drug-drug combinations. Some unregulated herbal supplements have been implicated in the onset of serotonin toxicity, however, there is currently minimal literature available on the potential for black cohosh to contribute to rhabdomyolysis and serotonin toxicity, in spite of its known serotonergic properties. CASE REPORT: A middle-aged woman presented to the emergency department with serotonin toxicity and rhabdomyolysis shortly after taking black cohosh supplements in the setting of long-term dual antidepressant use. The serotonin toxicity and rhabdomyolysis resolved with IV fluids, benzodiazepines, and discontinuation of the offending drugs. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Patients are sometimes not aware of how over-the-counter supplements might interact with their prescription medications. Female patients taking black cohosh to manage hot flashes and menopausal symptoms could be at risk for developing rhabdomyolysis and serotonin toxicity if they are also taking other serotonergic agents.

Herb-drug interactions: A short review on central and peripheral nervous system drugs.

Herbal medicines are widely perceived as natural and safe remedies. However, their concomitant use with prescribed drugs is a common practice, often undertaken without full awareness of the potential risks and frequently without medical supervision. This practice introduces a tangible risk of herb-drug interactions, which can manifest as a spectrum of consequences, ranging from acute, self-limited reactions to unpredictable and potentially lethal scenarios. This review offers a comprehensive overview of herb-drug interactions, with a specific focus on medications targeting the Central and Peripheral Nervous Systems. Our work draws upon a broad range of evidence, encompassing preclinical data, animal studies, and clinical case reports. We delve into the intricate pharmacodynamics and pharmacokinetics underpinning each interaction, elucidating the mechanisms through which these interactions occur. One pressing issue that emerges from this analysis is the need for updated guidelines and sustained pharmacovigilance efforts. The topic of herb-drug interactions often escapes the attention of both consumers and healthcare professionals. To ensure patient safety and informed decision-making, it is imperative that we address this knowledge gap and establish a framework for continued monitoring and education. In conclusion, the use of herbal remedies alongside conventional medications is a practice replete with potential hazards. This review not only underscores the real and significant risks associated with herb-drug interactions but also underscores the necessity for greater awareness, research, and vigilant oversight in this often-overlooked domain of healthcare.

Evidence of the interactions between immunosuppressive drugs used in autoimmune rheumatic diseases and Chinese herbal medicine: A scoping review.

OBJECTIVES: Chinese herbal medicine (CHM) has been shown to be effective in autoimmune rheumatic diseases, but harmful herb-drug interactions might be inherent. We aim to review the evidence regarding herb-drug interactions between immunosuppressive drugs used in autoimmune rheumatic diseases and CHM. METHODS: We searched PubMed, EMBASE and CINAHL from inception till 30 April 2023 using keywords that encompassed 'herb-drug interactions', 'herbs' and 'immunosuppressants'. Articles were included if they contained reports about interactions between immunosuppressive drugs used in the treatment of rheumatic diseases with CHM. Level of evidence for each pair of interaction was graded using the algorithm developed by Colalto. RESULTS: A total of 65 articles and 44 unique pairs of interactions were identified. HDIs were reported for cyclophosphamide, cyclosporine, tacrolimus, methotrexate, mycophenolic acid, glucocorticoids, sulfasalazine, tofacitinib and biologic disease-modifying antirheumatic drugs. Among these, cyclosporine (n = 27, 41.5%) and tacrolimus (n = 19, 29.2%) had the highest number of documented interactions. Hypericum perforatum had the highest level of evidence of interaction with cyclosporine and tacrolimus. Consumption reduced the bioavailability and therapeutic effects of the drugs. Schisandra sphenanthera had the highest level of evidence of interaction with tacrolimus and increased the bioavailability of the drug. Majority of the articles were animal studies. CONCLUSION: Overall level of evidence for the included studies were low, though interactions between cyclosporine, tacrolimus, Hypericum perforatum and Schisandra sphenanthera were the most and well-documented. Healthcare professionals should actively enquire about the concurrent use of CHM in patients, especially when drugs with a narrow therapeutic index are consumed.

Changing Trends Towards Herbal Supplements: An Insight into Safety and Herb-drug Interaction.

Herbs have been used as sustenance and medicine for a very long time, often in conjunction with other prescribed medications. Even though they are thought to be natural and secure, many of these herbs can interact with other medications and cause potentially dangerous adverse effects or decrease the benefits of the medication. The complex and diverse pharmacological functions carried out by the active ingredients in herbs unavoidably alter the pharmacokinetics of chemical drugs when administered in vivo. Drug transporter expression has a direct impact on how medications are absorbed, distributed, metabolized, and excreted in living organisms. Changes in substrate pharmacokinetics can affect the effectiveness and toxicity of a drug when the active ingredients of a herb inhibit or stimulate the expression of transporters. By reviewing published clinical and preclinical studies, this review aims to raise awareness of herbdrug interactions and discuss their evidence-based mechanisms and clinical consequences. More clinical information on herb-drug interactions is required to make choices regarding patient safety as the incidence and severity of herb-drug interactions are rising due to an increase in the use of herbal preparations globally.This review seeks to increase understanding of herb-drug interactions and explore their evidence-based mechanisms and clinical implications by reviewing published clinical and preclinical studies. The incidence and severity of herb-drug interactions are on the rise due to an increase in the use of herbal preparations worldwide, necessitating the need for more clinical data on these interactions in order to make decisions regarding patient safety. Healthcare workers and patients will become more alert to potential interactions as their knowledge of pharmacokinetic herb-drug interactions grows. The study's objective is to raise readers' awareness of possible interactions between herbal supplements and prescription medications who regularly take them.

In vivo assessment of black seed oil single dose on prednisolone pharmacokinetics.

OBJECTIVES: To investigate the effect of blackseed oil (BSO) single dose on prednisolone pharmacokinetics via p-gp inhibition. METHODS: Three groups of rats (n = 5) were orally administered the vehicle, verapamil (50 mg/kg) or BSO (5 ml/kg) 15 min prior to prednisolone (5 mg/kg) administration. Blood samples were collected over 24 h and quantified. Non-compartmental analysis was employed to calculate maximum plasma concentration (Cmax), area under the curve (AUC0-last), time to reach Cmax (Tmax), apparent clearance (CL/F), and half-life (t1/2). Statistical significance was considered at p<0.05. RESULTS: Prednisolone Cmax and AUC0-last decreased by 65% and 25% in the BSO group compared to the negative control (P < .0001, .0029, respectively) while they increased by 1.75-folds and 8-folds in verapamil group (P < .0001). Tmax was achieved at 0.16, 0.5, and 0.25 h in the negative control, verapamil, and BSO-treated groups, respectively. CL/F in the treatment group was 1.3-fold and 10-fold higher compared to the negative and positive control, respectively, whereas the t1/2 remained comparable. CONCLUSION: Administration of BSO decreased prednisolone Cmax and AUC0-last in rats indicating that there is a herb-drug interaction; however, p-gp inhibition cannot be concluded. Patients relying on folk medicine in chronic illnesses treatment might need to avoid combining BSO with prednisolone.

Pharmacokinetic and pharmacodynamic herb-drug interactions-part I. Herbal medicines of the central nervous system.

Unlike conventional drug substances, herbal medicines are composed of a complex of biologically active compounds. Therefore, the potential occurrence of herb-drug interactions is even more probable than for drug-drug interactions. Interactions can occur on both the pharmacokinetic and pharmacodynamic level. Herbal medicines may affect the resulting efficacy of the concomitantly used (synthetic) drugs, mainly on the pharmacokinetic level, by changing their absorption, distribution, metabolism, and excretion. Studies on the pharmacodynamic interactions of herbal medicines and conventional drugs are still very limited. This interaction level is related to the mechanism of action of different plant constituents. Herb-drug interactions can cause changes in drug levels and activities and lead to therapeutic failure and/or side effects (sometimes toxicities, even fatal). This review aims to provide a summary of recent information on the potential drug interactions involving commonly used herbal medicines that affect the central nervous system (Camellia, Valeriana, Ginkgo, Hypericum, Humulus, Cannabis) and conventional drugs. The survey databases were used to identify primary scientific publications, case reports, and secondary databases on interactions were used later on as well. Search keywords were based on plant names (botanical genera), officinal herbal drugs, herbal drug preparations, herbal drug extracts.

A Comparative GC/MS Analysis of Citrus Essential Oils: Unveiling the Potential Benefits of Herb-Drug Interactions in Preventing Paracetamol-Induced Hepatotoxicity.

Our study aimed to test the potential of Citrus oils in protecting against paracetamol (PAR)-induced hepatotoxicity. The essential oils of Pineapple sweet orange (OO), Murcott mandarin (MO), Red grapefruit (GO), and Oval kumquat (KO) were investigated using gas chromatography coupled with mass spectrometry (GC/MS). Twenty-seven compounds were identified, with monoterpene hydrocarbons being abundant class. d-Limonene had the highest percentage (92.98 %, 92.82 %, 89.75 %, and 94.46 % in OO, MO, GO, and KO, respectively). Hierarchical cluster analysis (HCA) and principal components analysis (PCA) revealed that octanal, linalool, germacrene D, and d-limonene were the principal discriminatory metabolites that segregated the samples into three distinct clusters. In vitro antioxidant capacities were ranged from 1.2-12.27, 1.79-5.91, and 235.05-585.28 µM Trolox eq/mg oil for 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic (ABTS), ferric-reducing antioxidant power (FRAP), and oxygen radical absorbance capacity (ORAC), respectively. In vivo, citrus oils exhibited a significant reduction in alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and nitric oxide (NO). Additionally, there was an increase in glutathione reductase (GSH), and the liver architecture was nearly normal. Molecular docking revealed that d-limonene exhibited a good inhibitory interaction with cytochrome P450 (CYP450) isoforms 1A2, 3A4, and 2E1, with binding energies of -6.17, -4.51, and -5.61 kcal/mol, respectively.

Antiproliferative and Anti-Inflammatory Activities of Deprungsith Formulation and Its Bioactive Compounds Against Mild Psoriasis and Potential of Metabolic Herb-Drug Interactions.

Psoriasis is an incurable, chronic and auto-immune skin disorder with a global prevalence rate of approximately 2-3%. The study investigated the antipsoriasis activities of Deprungsith formulation and its bioactive components and their potential for inhibitory activities on human cytochrome P450 (CYP450). HaCaT and peripheral blood mononuclear cells (PBMCs) from healthy volunteers (n = 9) and psoriasis patients (n = 10) were exposed to Deprungsith formulation (Thai traditional medicine for psoriasis consisting of 16 plants), ethyl p-methoxycinnamate (EPMC), ligustilide and cyclosporin for 24 and 48 h. The antiproliferative, cell apoptosis and cell cycle arrest activities were evaluated using MTT assay and flow cytometry, respectively. The pro-inflammatory cytokine mRNA expression levels were measured using real-time polymerase chain reaction (RT-PCR). The CYP450 inhibitory effect was investigated using a bioluminescent-based CYP450 assay. Deprungsith formulation and the bioactive compounds inhibited HaCaT cells and PBMCs with weak to moderate potencies. EPMC and ligustilide combination produced an additive effect. Most substances arrested cell transition at sub-G1 and S phases, leading to early and late apoptosis induction. With prolonged exposure (48 h), all test substances decreased PBMCs necrosis. The mRNA expression of all pro-inflammatory cytokines was downregulated. Deprungsith formulation, EPMC, ligustilide and ferulic acid inhibited CYP1A2, CYP2C9, CYP2D6 and CYP3A4 activities with weak to moderate potencies. Deprungsith formulation and bioactive components induced cell apoptosis by inhibiting cell transition at specific cell cycle phases, which was correlated with the mRNA downregulation of interleukin (IL-6, IL-12p19, IL-23) and tumor necrosis factor (TNF-α). There is a low risk of potential adverse drug reactions and toxicity due to CYP450 interaction when Deprungsith formulation is concurrently administered with modern medicines.

Concurrent use of herbal and prescribed medicine by patients in primary health care clinics, South Africa.

BACKGROUND: The use of herbal medicine (HM) as a self-management practice for treating various diseases has gained popularity worldwide. Consumers co-administer herbal products with conventional medicine without the knowledge of possible herb-drug interaction (HDI). AIM: This study aimed to assess patients' perception and use of HM and their knowledge of HDI. SETTING: Participants attending primary health care (PHC) clinics in three provinces (Gauteng, Mpumalanga and Free State), South Africa, were recruited. METHODS: Focus group discussions comprising a total of thirty (N = 30) participants were conducted using a semi-structured interview guide. Discussions were audio-recorded and then transcribed verbatim. Data were analysed using thematic content analysis. RESULTS: Reasons for using HM, sources of information on HM, co-administration of HM and prescribed medicine, disclosure of the use of HM, PHC nurses' attitudes and not having time to engage were frequently discussed. Respondents' lack of knowledge and perceptions about HDI and their dissatisfaction with prescribed medicine because of experienced side effects were also discussed. CONCLUSION: Because of the lack of discussions and non-disclosure about HM in PHC clinics, patients are at risk of experiencing HDIs. Primary health care providers should regularly enquire about HM use on every patient, to identify and prevent HDIs. The lack of knowledge about HDIs by patients further compromises the safety of HM.Contribution: The results highlighted the lack of knowledge of HDI by patients thus assisting the healthcare stakeholders in South Africa to implement measures to educate patients attending PHC clinics.

Interactions between complementary medicines and drugs used in primary care and oral COVID-19 antiviral drugs.

BACKGROUND: Patient harm resulting from drug interactions between conventional and traditional or complementary medicines (CM) are avoidable. OBJECTIVE: To provide a clinical overview of a selection of CM interactions with drugs commonly used in Australian general practice or in the management of COVID-19. DISCUSSION: Many herb constituents are substrates for cytochrome P450 enzymes, and inducers and/or inhibitors of transporters such as P-glycoprotein. Hypericum perforatum (St John's Wort), Hydrastis canadensis (golden seal), Ginkgo biloba (ginkgo) and Allium sativum (garlic) are reported to interact with many drugs. Simultaneous administration of certain anti-viral drugs with zinc compounds and several herbs should also be avoided. Preventing and identifying unwanted CM-drug interactions in primary care requires vigilance, access to CM-drug interaction checkers and excellent communication skills. Potential risks from interactions should be balanced against the potential benefits of continuing the drug and/or CM and involve shared decision making.

Biotransformation and brain distribution of the anti-COVID-19 drug molnupiravir and herb-drug pharmacokinetic interactions between the herbal extract Scutellaria formula-NRICM101.

The aim of this study was to explore the effects of herbal drug pharmacokinetic interactions on the biotransformation of molnupiravir and its metabolite ß-D-N4-hydroxycytidine (NHC) in the blood and brain. To investigate the biotransformation mechanism, a carboxylesterase inhibitor, bis(4-nitrophenyl)phosphate (BNPP), was administered. Not only molnupiravir but also the herbal medicine Scutellaria formula-NRICM101 is potentially affected by coadministration with molnupiravir. However, the herb-drug interaction between molnupiravir and the Scutellaria formula-NRICM101 has not yet been investigated. We hypothesized that the complex bioactive herbal ingredients in the extract of the Scutellaria formula-NRICM101, the biotransformation and penetration of the bloodbrain barrier of molnupiravir are altered by inhibition of carboxylesterase. To monitor the analytes, ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLCMS/MS) coupled with the microdialysis method was developed. Based on the dose transfer from humans to rats, a dose of molnupiravir (100 mg/kg, i.v.), molnupiravir (100 mg/kg, i.v.) + BNPP (50 mg/kg, i.v.), and molnupiravir (100 mg/kg, i.v.) + the Scutellaria formula-NRICM101 extract (1.27 g/kg, per day, for 5 consecutive days) were administered. The results showed that molnupiravir was rapidly metabolized to NHC and penetrated into the brain striatum. However, when concomitant with BNPP, NHC was suppressed, and molnupiravir was enhanced. The blood-to-brain penetration ratios were 2% and 6%, respectively. In summary, the extract of the Scutellaria formula-NRICM101 provides a pharmacological effect similar to that of the carboxylesterase inhibitor to suppress NHC in the blood, and the brain penetration ratio was increased, but the concentration is also higher than the effective concentration in the blood and brain.