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Organic cation transporter 1 (OCT1, gene symbol: SLC22A1) is mainly responsible for the hepatic uptake of various cationic drugs, closely associated with drug-induced liver injury (DILI). Screening and identifying potent OCT1 inhibitors with little toxicity in natural products is of great value in alleviating OCT1-mediated liver injury. Flavonoids, a group of polyphenols commonly found in foodstuffs and herbal products, have been reported to cause transporter-mediated food/herb-drug interactions (FDIs). Our objective was to investigate potential inhibitors of OCT1 from 96 flavonoids, evaluate the hepatoprotective effects on retrorsine-induced liver injury, and clarify the structure-activity relationships of flavonoids with OCT1. Thirteen flavonoids exhibited significant inhibition (>50%) on OCT1 in OCT1-HEK293 cells. Among them, the five strongest flavonoid inhibitors (IC50 < 10 µM), including α-naphthoflavone, apigenin, 6-hydroxyflavone, luteolin, and isosilybin markedly decreased oxaliplatin-induced cytotoxicity. In retrorsine-induced liver injury models, they also reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) to different levels, the best of which was 6-hydroxyflavone. The pharmacophore model clarified that hydrogen bond acceptors at the 4,8,5' position might play a vital role in the inhibitory effect of flavonoids on OCT1. Taken together, our findings would pave the way to predicting the potential risks of flavonoid-related FDIs in humans and optimizing flavonoid structure to alleviate OCT1-mediated liver injury.

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Apiole (1-allyl-2,5-dimethoxy-3,4-methylenedioxybenzene) and parsley leaves ethanolic extract containing it inhibit the rat liver microsomal ethoxy- and methoxyresorufin-O-deacetylase activities associated with cytochrome P450 (CYP) 1A1 and 1A2, respectively. Cytochrome P4501A subfamily metabolizes environmental mutagens and several drugs, leading to the formation of mutagenic metabolites. Docking analysis showed that residue Phe123 within the active site of the CYP1A1 enzyme is bound to apiole through a π/π stacking of its benzene ring. In the case of 1A2, its Phe226 interacts with the dioxolane ring of apiole. Furthermore, apiole behaves as a mixed-type inhibitor of bacterial human recombinant CYP1A1. To explore one of the possible biological implications of this inhibitory effect, we tested the capacity of apiole and the parsley ethanolic extract to interfere with the mutagenicity of the promutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) metabolized by CYP1A subfamily. As expected, both apiole and the plant extract reduced the number of revertant colonies of Salmonella typhimurium TA98 Ames strain after exposure to MeIQx, reaching a 78 % and 100 % reduction, respectively. Neither apiol nor parsley extract were mutagenic to the TA98 strain. We speculate that consuming apiole, a constituent of edible herbs, in conjunction with the utilization of pharmaceuticals metabolized by the CYP1A subfamily, may result in herb-drug interactions. Furthermore, the consumption of apiole by individuals who regularly ingest fresh vegetables may contribute to the low incidence of cancer observed in those who adhere to such a dietary regimen.

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AIM: Yokukansan is one of the most frequently used herbal medicines that can improve the behavioral and psychological symptoms of dementia. In this exploratory study, we investigated whether yokukansan affects the steady-state blood concentrations of donepezil, risperidone, and the major metabolites of both drugs in a real-world clinical setting. METHODS: A non-randomized, open-label, single-arm study examining drug-drug interactions was conducted. Fifteen dementia patients taking donepezil for at least 4 weeks and eight schizophrenia patients taking risperidone for at least 2 weeks were orally administered 2.5 g of yokukansan three times a day before or between meals, and blood samples were collected before and 8 weeks after starting co-treatment with yokukansan. Plasma concentrations of donepezil, risperidone, and each metabolite were measured using high-performance liquid chromatography-tandem mass spectrometry and compared before and after the 8-week administration of yokukansan. RESULTS: The plasma concentrations of donepezil and its metabolites (6-O-desmethyl-donepezil, 5-O-desmethyl-donepezil, and donepezil-N-oxide), risperidone, and its metabolite paliperidone did not differ before and after the 8-week treatment with yokukansan. CONCLUSIONS: The findings of this study show that the concomitant use of yokukansan may have little clinical impact on the steady-state blood levels of donepezil and risperidone in patients with dementia or schizophrenia.

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Background: Combination therapy was associated with an increased risk of drug- drug interactions (DDIs) in patients with type 2 diabetes mellitus (T2DM). The present study aimed to investigate the epidemiology of potential DDIs (pDDIs), including potential chemical drug-drug interactions (pCDIs) and potential herb-drug interactions (pHDIs), and classify the influencing factors of pDDIs in these patients. Methods: A retrospective study of the epidemiology of pDDIs among T2DM hospitalized patients older than 18 years and treated with at least two drugs during hospitalization was conducted over a 12-month period in 2019. PDDIs were identified with C (monitor therapy), D (consider therapy modification), and X (avoid combination) risk ratings. Binary logistic regression was used to analyze the risk factors of pDDIs. Results: A total of 6796 pDDIs were identified from 737 T2DM hospitalized patients during hospitalization, with 0.87% classified as X risk rating, 13.39% as D risk rating. Additionally, 1753 pDDIs were identified after discharge, with 0.11% as X and 25.73% as D risk rating. The drug-drug association networks showed that the majority of pCDIs were associated with cardiovascular system drugs. Chlorphenamine-potassium chloride and danshen-warfarin were the most prevalent interacting pairs of pCDIs and pHDIs with X rating during hospitalization. Multivariate analysis indicated that the likelihood of developing over 4 pDDIs was significantly higher among T2DM patients who had received over 8 medications. The presence of pDDIs after discharge was strongly associated with the complications of T2DM and the number of discharge medications. Conclusions: T2DM patients were frequently exposed to pDDIs, including pCDIs and pHDIs, both during hospitalization and after discharge. Multi-drug combination was the primary risk factor for pDDIs. Strategies such as enhancing the monitoring and warning for pDDIs, increasing clinical pharmacological experience, as well as developing universally applicable clinical guidelines for pDDIs may be beneficial in reducing the incidence of potentially harmful drug-combinations.

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Objectives: In recent years, especially with the Coronavirus Disease of 2019 (COVID-19) pandemic, the use of herbal products for various health problems has been increasing worldwide. This study aimed to determine the frequency of herbal product/dietary supplement use, the most used products, and the factors affecting the use of these products in patients who applied to the Chest Diseases Clinic. Materials and Methods: This descriptive survey study was conducted at Chest Diseases Clinic using a face-to-face interview technique. Adult individuals with subacute respiratory complaints for > 3 weeks or a diagnosis of chronic chest disease were included in the study. The questionnaire form included questions about personal characteristics, data related to disease and treatment, use of herbal products/dietary supplements, and attitudes toward these products. A total of 444 participants with all the data included in the study. Descriptive statistics, chi-square, and binary logistic regression tests were used. Results: It was determined that 49.3% of the participants used herbal products/dietary supplements, and the most frequently used products were honey, linden, ginger, lemon, and carob. According to the results of the binary logistic regression test, it was determined that patients over 60 years old [odds ratio (OR)= 2.0, 95% confidence interval (Cl): 1.1-3.8, p= 0.042], those with a high education level (OR= 2.0, 95% Cl: 1.1-3.6, p= 0.018), those who live in urban (OR= 1.8, 95% Cl: 1.1-3.0, p= 0.018), and those with a diagnosis of post-COVID syndrome (OR= 2.7, 95%, Cl: 1.3-5.5, p= 0.007) are more likely to use these products. It was determined that 57.9% of the participants used these products to relieve the symptoms of the disease. Conclusion: Considering the high probability of using these products in patients with respiratory tract disease, it is essential for public health that health professionals question the use of these products and provide counseling on this issue.

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Multidrug and toxin extrusion protein 1 (MATE1), an efflux transporter mainly expressed in renal proximal tubules, mediates the renal secretion of organic cationic drugs. The inhibition of MATE1 will impair the excretion of drugs into the tubular lumen, leading to the accumulation of nephrotoxic drugs in the kidney and consequently potentiating nephrotoxicity. Screening and identifying potent MATE1 inhibitors can predict or minimize the risk of drug-induced kidney injury. Flavonoids, a group of polyphenols commonly found in foodstuffs and herbal products, have been reported to cause transporter-mediated food/herb-drug interactions. Our objective was to investigate the inhibitory effects of flavonoids on MATE1 in vitro and in vivo and to assess the effects of flavonoids on cisplatin-induced kidney injury. Thirteen flavonoids exhibited significant transport activity inhibition (>50%) on MATE1 in MATE1-MDCK cells. Among them, the six strongest flavonoid inhibitors, including irisflorentin, silymarin, isosilybin, sinensetin, tangeretin, and nobiletin, markedly increased cisplatin cytotoxicity in these cells. In cisplatin-induced in vivo renal injury models, irisflorentin, isosilybin, and sinensetin also increased serum creatinine and blood urea nitrogen levels to different degrees, especially irisflorentin, which exhibited the most potent nephrotoxicity with cisplatin. The pharmacophore model indicated that the hydrogen bond acceptors at the 3, 5, and 7 positions may play a critical role in the inhibitory effect of flavonoids on MATE1. Our findings provide helpful information for predicting the potential risks of flavonoid-containing food/herb-drug interactions and avoiding the exacerbation of drug-induced kidney injury via MATE1 mediation.

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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.

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BACKGROUND: The use of herbal medicines is on the rise throughout the world due to their perceived safety profile. However, incidences of herb-drug, herb-herb and herb-food interactions considering safety aspects have opened new arenas for discussion. OBJECTIVE: The current study aims to provide comprehensive insights into the various types of herb interactions, the mechanisms involved, their assessment, and historical developments, keeping herbal safety at the central point of discussion. METHODS: The authors undertook a focused/targeted literature review and collected data from various databases, including Science Direct, Wiley Online Library, Springer, PubMed, and Google Scholar. Conventional literature on herbal remedies, such as those by the WHO and other international or national organizations. RESULTS: The article considered reviewing the regulations, interaction mechanisms, and detection of herb-herb, herb-drug and herb-food interactions in commonly used yet vital plants, including Glycyrrhiza glabra, Mentha piperita, Aloe barbadensis, Zingiber officinale, Gingko biloba, Withania somnifera, etc. The study found that healthcare professionals worry about patients not informing them about their herbal prescriptions (primarily used with conventional treatment), which can cause herb-drug/herb-food/herb-herb interactions. These interactions were caused by altered pharmacodynamic and pharmacokinetic processes, which might be explained using in-vivo, in-vitro, in-silico, pharmacogenomics, and pharmacogenetics. Nutrivigilance may be the greatest method to monitor herb-food interactions, but its adoption is limited worldwide. CONCLUSION: This article can serve as a lead for clinicians, guiding them regarding herb-drug, herb-food, and herb-herb interactions induced by commonly consumed plant species. Patients may also be counseled to avoid conventional drugs, botanicals, and foods with a restricted therapeutic window.

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BACKGROUND: Herb-drug interactions may result in increased adverse drug reactions or diminished drug efficacy, especially for drugs with a narrow therapeutic index such as warfarin. The current study investigates the effects of sodium ferulate for injection (SFI) on anticoagulation of warfarin from aspects of pharmacodynamics and pharmacokinetics in rats and predicts the risk of the combination use. METHODS: Rats were randomly divided into different groups and administered single- or multiple-dose of warfarin (0.2 mg/kg) with or without SFI of low dose (8.93 mg/kg) or high dose (26.79 mg/kg). Prothrombin time (PT) and activated partial thromboplastin time (APTT) were detected by a blood coagulation analyzer, and international normalized ratio (INR) values were calculated. UPLC-MS/MS was conducted to measure concentrations of warfarin enantiomers and pharmacokinetic parameters were calculated by DAS2.0 software. RESULTS: The single-dose study demonstrated that SFI alone had no effect on coagulation indices, but significantly decreased PT and INR values of warfarin when the two drugs were co-administered (P < 0.05 or P < 0.01), while APTT values unaffected (P > 0.05). Cmax and AUC of R/S-warfarin decreased but CL increased significantly in presence of SFI (P < 0.01). The multiple-dose study showed that PT, APTT, INR, and concentrations of R/S-warfarin decreased significantly when SFI was co-administered with warfarin (P < 0.01). Warfarin plasma protein binding rate was not significantly changed by SFI (P > 0.05). CONCLUSIONS: The present study implied that SFI could accelerate warfarin metabolism and weaken its anticoagulation intensity in rats.

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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.

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Introducción: El 50% de la población mundial usa tratamientos alternativos como productos herbarios. El 20% los consume de manera simultánea con algún tratamiento farmacológico para el control la Diabetes Mellitus tipo 2; enfermedad prevalente en adultos mayores. Es escasa la información acerca de las interacciones medicamentosas que pudieran producirse, siendo responsables de más de 7,000 muertes al año. Objetivo: Identificar los productos herbarios de mayor consumo del Adulto Mayor con Diabetes Mellitus Tipo 2, en Chapulco, Puebla, México y describir las posibles interacciones medicamentosas entre fármaco hipoglucemiante ­ producto herbario reportados en la literatura científica. Metodología: Estudio observacional, prolectivo, transversal, descriptivo, en una población de 35 adultos mayores diabéticos, con edad promedio de 70±7 años. Para la identificación de los productos herbarios de uso común y sus aplicaciones terapéuticas se aplicó el cuestionario U-PLANMED. Resultados: Se identificaron 50 productos herbarios y 18 combinaciones entre estos a la vez. El 40% de los participantes consumen simultáneamente más de dos productos herbarios con uno o dos fármacos hipoglucemiantes. Entre los productos de mayor consumo se encuentran el nopal (Opuntia ficus-indica L.), la manzanilla (Matricaria chamomilla L.) y el zacate de limón (Cymbopogon citratus DC. Stapf.). Las interacciones medicamentosas potenciales identificadas, principalmente en estudios experimentales en animales, sugieren que, existe una acción hipoglucemiante del producto herbario al aumentar la capacidad orgánica sobre la secreción/liberación de insulina endógena. Conclusiones: Se ha evidenciado la presencia de interacciones medicamentosas ante el consumo simultaneo de fármacos prescritos para el control de la diabetes mellitus tipo 2 con productos herbarios. Es necesario que, los profesionales en atención a la salud identifiquen el uso de dichos productos y orienten a los adultos mayores sobre las posibles repercusiones en los niveles de glucosa ante el consumo.

Introduction: 50% of the world's population uses alternative treatments such as herbal products. Twenty percent use them in conjunction with some form of pharmacological treatment to control type 2 diabetes mellitus, a disease prevalent in older adults. There is little information on the drug interactions that may occur, which are responsible for more than 7,000 deaths per year. Objective: To identify the most consumed herbal products among older adults with type 2 diabetes mellitus in Chapulco, Puebla, Mexico, and to describe the possible drug-drug interactions between hypoglycemic drugs and herbal products reported in the scientific literature. Methodology: Observational, prospective, cross-sectional, descriptive study in a population of 35 diabetic older adults with a mean age of 70±7 years. The U-PLANMED questionnaire was used to identify commonly used herbal products and their therapeutic applications. Results: Fifty herbal products and 18 combinations of them were identified. Forty percent of the participants used more than two herbal products simultaneously with one or two hypoglycemic drugs. The most used products included prickly pear cactus (Opuntia ficus-indica L.), chamomile (Matricaria chamomilla L.), and lemon grass (Cymbopogon citratus DC. Stapf.). Potential drug-drug interactions identified mainly in experimental animal studies suggest that there is a hypoglycemic effect of the herbal product by increasing the organic capacity on endogenous insulin secretion/release. Conclusions: The presence of drug-drug interactions has been demonstrated with the simultaneous consumption of drugs prescribed for the control of type 2 diabetes mellitus with herbal products. It is necessary for health care professionals to recognize the use of such products and to inform older adults about the possible repercussions on glucose levels when consuming them.

Introdução: 50% da população mundial utiliza tratamentos alternativos como os produtos à base de plantas. Vinte por cento utilizam-nos em conjunto com algum tipo de tratamento farmacológico para controlar a diabetes mellitus tipo 2, uma doença prevalente em adultos mais velhos. Há pouca informação sobre as interacções medicamentosas que podem ocorrer e que são responsáveis por mais de 7.000 mortes por ano. Objetivos: Identificar os produtos fitoterápicos mais consumidos entre os idosos com diabetes mellitus tipo 2 em Chapulco, Puebla, México, e descrever as possíveis interações medicamentosas entre medicamentos hipoglicemiantes e produtos fitoterápicos relatados na literatura científica. Metodologia: Estudo observacional, prospetivo, transversal e descritivo numa população de 35 idosos diabéticos com uma idade média de 70±7 anos. O questionário U-PLANMED foi utilizado para identificar os produtos fitoterápicos mais utilizados e suas aplicações terapêuticas. Resultados: Foram identificados 50 produtos à base de plantas e 18 combinações dos mesmos. Quarenta por cento dos participantes utilizaram mais de dois produtos à base de plantas em simultâneo com um ou dois medicamentos hipoglicemiantes. Os produtos mais utilizados foram o cato de figo da Índia (Opuntia ficus-indica L.), a camomila (Matricaria chamomilla L.) e o capim-limão (Cymbopogon citratus DC. Stapf.). As potenciais interacções medicamentosas identificadas principalmente em estudos experimentais em animais sugerem que existe um efeito hipoglicémico do produto à base de plantas através do aumento da capacidade orgânica na secreção/libertação de insulina endógena. Conclusões: A presença de interacções medicamentosas foi demonstrada com o consumo simultâneo de medicamentos prescritos para o controlo da diabetes mellitus tipo 2 com produtos à base de plantas. É necessário que os profissionais de saúde reconheçam o uso de tais produtos e informem os idosos sobre as possíveis repercussões nos níveis de glicose ao consumi-los.

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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.

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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.

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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.

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Aim: We aimed to systematically evaluate the prevalence and clinical characteristics of adverse events associated with the adaptogens and antidepressant drug interactions in a retrospective chart review. Methodology: A total of 1,816 reports of adverse events were evaluated. Cases were included in the analysis if the pharmacoepidemiological analysis showed the presence of a high probability of a causal relationship between an adaptogen and antidepressant interaction and the occurrence of adverse events. The following data were extracted from the reports: age, sex, antidepressant, plant products containing adaptogens, other concomitant medications, and clinical consequences of the interactions and their possible mechanisms. Results: Adaptogens were involved in 9% of adverse events associated with the concomitant use of antidepressants and other preparations. We identified 30 reports in which side effects presented a causal relationship with the use of antidepressants and adaptogens. Here, we present the list of adaptogens with the corresponding antidepressants and the side effects caused by their interactions: Withania somnifera: reboxetine (testicle pain and ejaculatory dysfunctions), sertraline (severe diarrhea), escitalopram (myalgia, epigastric pain, nausea, vomiting, restless legs syndrome, and severe cough), and paroxetine (generalized myalgia, ophthalmalgia, and ocular hypertension); Eleutherococcus senticosus: duloxetine (upper gastrointestinal bleeding), paroxetine (epistaxis), sertraline (vaginal hemorrhage), and agomelatine (irritability, agitation, headache, and dizziness); Schisandra chinensis: bupropion (arthralgia and thrombocytopenia), amitriptyline (delirium), and fluoxetine (dysuria); Tribulus terrestris: citalopram (generalized pruritus), escitalopram (galactorrhea), and trazodone (psoriasis relapse); Coptis chinensis: mianserin (arrhythmias), mirtazapine (edema of lower limbs and myalgia), and fluoxetine (gynecomastia); Cimicifuga racemosa: mianserin (restless legs syndrome), paroxetine (gynecomastia and mastalgia), and venlafaxine (hyponatremia); Bacopa monnieri: agomelatine (back pain and hyperhidrosis) and moclobemide (myocardial infarction); Gynostemma pentaphyllum: duloxetine (back pain); Cordyceps sinensis: sertraline (upper gastrointestinal bleeding); Lepidium meyenii: mianserin (restless legs syndrome); and Scutellaria baicalensis: bupropion (seizures). Conclusion: Clinicians should monitor the adverse events associated with the concomitant use of adaptogens and antidepressant drugs in patients with mental disorders. Aggregation of side effects and pharmacokinetic interactions (inhibition of CYP and p-glycoprotein) between those medicines may result in clinically significant adverse events.

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Dasatinib (DAS) is a narrow therapeutic index drug and novel oral multitarget inhibitor of tyrosine kinase and approved for the first-line therapy for chronic myelogenous leukemia (CML) and Philadelphia chromosome (Ph + ) acute lymphoblastic leukemia (ALL). DAS, a known potent substrate of cytochrome (CYP) 3A, P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) and is subject to auto-induction. The dietary supplementation of sinapic acid (SA) or concomitant use of SA containing herbs/foods may alter the pharmacokinetics as well as pharmacodynamics of DAS, that may probably lead to potential interactions. Protein expression in rat hepatic and intestinal tissues, as well as the in vivo pharmacokinetics of DAS and the roles of CYP3 A2 and drug transporters Pgp-MDR1 and BCPR/ABCG2, suggested a likely interaction mechanism. The single dose of DAS (25 mg/kg) was given orally to rats with or without SA pretreatment (20 mg/kg p.o. per day for 7 days, n = 6). The plasma concentration of DAS was estimated by using Ultra-High-Performance Liquid Chromatography Mass spectrometry (UHPLC-MS/MS). The in vivo pharmacokinetics and protein expression study demonstrate that SA pretreatment has potential to alter the DAS pharmacokinetics. The increase in Cmax, AUC and AUMC proposes increase in bioavailability and rate of absorption via modulation of CYP3 A2, PgP-MDR1 and BCPR/ABCG2 protein expression. Thus, the concomitant use of SA alone or with DAS may cause serious life-threatening drug interactions.

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BACKGROUND: Herbal medicine is commonly integrated with conventional medicine in Saudi Arabia, especially for the management of digestive disorders. However, the majority of Saudis use herbal remedies without prior consultation with a physician, which raises concerns about their appropriate and safe use. The aim of this study was to assess the level of awareness among the Saudi population regarding the proper utilization and potential adverse effects of frequently used herbs for the treatment of gastrointestinal (GI) diseases. METHODS: A cross-sectional survey was conducted in Saudi Arabia from January to March 2021. An electronic self-administered questionnaire was distributed. RESULTS: A total of 543 participants from different age groups, educational levels, and cities across Saudi Arabia completed the study questionnaire. The most commonly used herbs at home by the participants were: myrrh, parsley, black seed, chamomile, mint, anise, clove, and green tea. 57.7% of the participants perceived herbs as safer than conventional medicines; 27.3% reported that using herbal remedies over conventional medicine was a family tradition, and 21.4% used herbs because they were cheaper than conventional medicines. CONCLUSION: Herbal remedies, including myrrh, parsley, blackseed, chamomile, mint, and anise, are commonly employed for the treatment of gastrointestinal disorders in Saudi Arabia. However, the knowledge level of participants regarding potential side effects and drug-herb interactions was found to be deficient. As such, there is a pressing need for educational campaigns and community awareness programs to elucidate the proper usage of herbal remedies and to caution against their potential adverse effects.

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Most of the currently available drugs are derived from natural sources, but they are used only after extensive chemical modifications to improve their safety and efficacy. Natural products are used in health supplements and cosmetic preparations and have been used as auxiliary drugs or alternative medicines. When used in combination with conventional drugs, these herbal products are known to alter their pharmacokinetics and pharmacodynamics, reducing their therapeutic effects. Moreover, herb-drug interactions (HDIs) may have serious side effects, which is one of the major concerns in health practice. It is postulated that HDIs affect the pathways regulating cytochrome P450 enzymes (CYPs). Betanin, the chief pigment of red beetroot (Beta vulgaris L.), has various types of pharmacological activity, such as anti-inflammatory, antioxidant, and anticancer effects. However, the potential risk of HDIs for betanin has not yet been studied. Thus, we aimed to predict more specific HDIs by evaluating the effects of betanin on CYPs (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), the major phase I metabolic enzymes, using fluorescence-/luminescence-based assays. Our results showed that betanin inhibited CYP3A4 activity in a dose-dependent manner (IC50 = 20.97 µΜ). Moreover, betanin acted as a competitive inhibitor of CYP3A4, as confirmed by evaluating Lineweaver-Burk plots (Ki value = 19.48 µΜ). However, no significant inhibitory effects were observed on other CYPs. Furthermore, betanin had no significant effect on CYP1A2, CYP2B6, or CYP2C9 induction in HepG2 cells. In conclusion, betanin acted as a competitive inhibitor of CYP3A4, and thus it should be used cautiously with other drugs that require metabolic enzymes as substrates. Additional in vivo studies and clinical trials are needed to further elucidate the HDIs of betanin.

RESUMEN

Overweight and obesity prevalence has increased worldwide. Apart from conventional approaches, people also resort to botanical supplements for reducing body weight, although several adverse events have been associated with these products. In this context, the present study aimed at evaluating the toxicity of Garcinia cambogia-based products and shedding light on the mechanisms involved. The suspected hepatotoxic reactions related to G. cambogia-containing products collected within the Italian Phytovigilance System (IPS) were examined. Then, an in vitro study was performed to evaluate the possible mechanisms responsible for the liver toxicity, focusing on the modulation of oxidative stress and Nrf2 expression. From March 2002 to March 2022, the IPS collected eight reports of hepatic adverse reactions related to G. cambogia, which exclusively involved women and were mostly severe. The causality assessment was probable in three cases, while it was possible in five. In the in vitro experiments, a low cytotoxicity of G. cambogia was observed. However, its combination with montelukast greatly reduced cell viability, increased the intracellular ROS levels, and affected the cytoplasmic Nrf2 expression, thus suggesting an impairment of the antioxidant and cytoprotective defenses. Overall, our results support the safety concerns about G. cambogia-containing supplements and shed light on the possible mechanisms underpinning its hepatotoxicity.

RESUMEN

The use of herbal medicines is increasing worldwide. While the safety profile of many herbal medicines is promising, the data in the literature show important interactions with conventional drugs that can expose individual patients to high risk. The aim of this study was to investigate the experience of the use of herbal medicines and preparations and the risks of interactions between herbal and conventional medicines among Latvian citizens. Data were collected between 2019 and 2021 using a structured questionnaire designed for pharmacy customers in Latvia. Electronic databases such as Drugs.com, Medscape, and European Union herbal monographs were reviewed for the risk of drug interactions and potential side effects when herbal medicines were involved. The survey included 504 respondents. Of all the participants, 77.8% used herbal preparations. Most of the participants interviewed used herbal remedies based on the recommendation of the pharmacist or their own initiative. A total of 38.3% found the use of herbal remedies safe and harmless, while 57.3% of respondents regarded the combination of herbal and regular drugs as unsafe. The identified herbal medicines implicated in the potential risk of serious interactions were grapefruit, St. John's wort, and valerian. As the risks of herb-drug interactions were identified among the respondents, in the future, both pharmacy customers and healthcare specialists should pay more attention to possible herb-drug interactions of over-the-counter and prescription medications.

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