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Up to 1/2 of outpatients prescribed clozapine may be partially/fully non-adherent, based on therapeutic drug monitoring (TDM). Three indices for measuring partial/full non-adherence are proposed a: 1) clozapine concentration/dose (C/D) ratio which drops to half or more of what is expected in the patient; 2) clozapine/norclozapine ratio that becomes inverted; and 3) clozapine concentration that becomes non-detectable. These 3 proposed indices are based on a literature review and 17 cases of possible non-adherence from 3 samples: 1) an inpatient study in a Chinese hospital, 2) an inpatient randomized clinical trial in a United States hospital, and 3) and a Uruguayan outpatient study. The first index of non-adherence is a clozapine C/D ratio which is less than half the ratio corresponding to the patient's specific ancestry group and sex-smoking subgroup. Knowing the minimum therapeutic dose of the patient based on repeated TDM makes it much easier to establish non-adherence. The second index is inverted clozapine/norclozapine ratios in the absence of alternative explanations. The third index is undetectable concentrations. By using half-lives, the chronology of the 3 indices of non-adherence was modeled in two patients: 1) the clozapine C/D ratio dropped to ≥1/2 of what is expected from the patient (around day 2); 2) the clozapine/norclozapine ratio became inverted (around day 3); and 3) the clozapine concentration became undetectable by the laboratory (around days 9–11). Prospective studies should further explore these proposed clozapine indices in average patients, poor metabolizers (3 presented) and ultrarapid metabolizers (2 presented). [Display omitted] [ABSTRACT FROM AUTHOR]

Clozapine was first manufactured in China in 1976. Clozapine is currently used not only for treatment-refractory schizophrenia (TRS), but also continues to be used in the treatment of patients with non-TRS and other mental disorders; moreover, low-dose clozapine is also used in sedative-hypnotic therapy and in combination with other drugs. There is need for studies in China using various titrations and assessing their risk for myocarditis and aspiration pneumonia. The Chinese clozapine package insert will also greatly benefit from these changes. [ABSTRACT FROM AUTHOR]

Copyright of Actualités Pharmaceutiques is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Actualités Pharmaceutiques is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Actualités Pharmaceutiques is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Actualités Pharmaceutiques is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Actualités Pharmaceutiques is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

[Display omitted] • Commercial precoated PAMPA is the most sensitive system for evaluating excipient effects. • PermeaPadTM is applicable to highly cytotoxic excipients owing to its high tolerance to excipient concentrations. • Caco-2 is a robust cell line that can be used to evaluate excipients at relatively high concentrations. • Most evaluated excipients did not affect drug membrane permeation at clinically used concentrations. The effects of pharmaceutical excipients on intestinal drug absorption have been highlighted and careful excipient selection is required to develop biologically equivalent formulations. This study aimed to evaluate the effects of excipients on drug permeability and compare the characteristics of in vitro screening methods. Three in vitro models, the commercial precoated parallel artificial membrane permeability assay (PAMPA), PermeaPadTM, and Caco-2 monolayer, were used to evaluate the effects of 14 excipients on the permeability of several drugs with different biopharmaceutical classification system classes. Concentration-dependent effects were analyzed to distinguish non-specific effects. The permeability of low-permeability drugs was increased by excipients such as hydroxypropyl cellulose and povidone K30 in the precoated PAMPA model, whereas PermeaPadTM maintained membrane integrity at higher concentrations. Conversely, croscarmellose sodium and sodium lauryl sulfate (SLS) decreased the permeability of highly permeable drugs in both precoated PAMPA and PermeaPadTM assays in a concentration-dependent manner. In Caco-2 monolayer assays, most excipients showed minimal effects on drug permeability. However, SLS significantly reduces the permeability of highly permeable drugs at concentrations above the critical micelle concentration, thereby compromising the integrity of the cell monolayer. Our results suggested that most of excipients, except SLS, did not affect the membrane permeation of drugs at clinically used concentrations. The pre-coated PAMPA model demonstrated high sensitivity to excipient effects, making it suitable for conservative evaluation. The PermeaPadTM and Caco-2 models allowed assessment at higher excipient concentrations, with PermeaPadTM being particularly useful for excipients that cause toxicity in Caco-2 cells. [ABSTRACT FROM AUTHOR]

Sunitinib, a novel anti-tumor small molecule targeting VEGFR, is prescribed for advanced RCC and GISTs. Sunitinib is primarily metabolized by the CYP3A enzyme. It is well-known that dexamethasone serves as a potent inducer of this enzyme system. Nonetheless, the effect of dexamethasone on sunitinib metabolism remains unclear. This study examined the effect of dexamethasone on the pharmacokinetics of sunitinib and its metabolite N-desethyl sunitinib in rats. The plasma levels of both compounds were measured using UHPLC-MS/MS. Pharmacokinetic parameters and metabolite ratio values were calculated. Compare to control group, the low-dose dexamethasone group and high-dose dexamethasone group decreased the AUC (0-t) values of sunitinib by 47 % and 45 %, respectively. Meanwhile, the AUC (0-t) values of N-desethyl sunitinib were increased by 2.2-fold and 2.4-fold in low-dose dexamethasone group and high-dose dexamethasone group, respectively. The CL values for sunitinib were both approximately 45 % higher in the two dexamethasone groups. Remarkably, metabolite ratio values increased over 5-fold in both low-dose dexamethasone group and high-dose dexamethasone group, indicating a significant enhancement of sunitinib metabolism by dexamethasone. Moreover, the total levels of sunitinib and its metabolite are also significantly increased. The impact of interactions on sunitinib metabolism, as observed with CYP3A inducers such as dexamethasone, is a crucial consideration for clinical practice. To optimize the dosage and prevent adverse drug events, therapeutic drug monitoring can be employed to avoid the toxicity from such interactions. • The CYP3A inducer dexamethasone altered the pharmacokinetics of sunitinib and its metabolite in rat. • Both the low-dose and high-dose dexamethasone increased the metabolism of sunitinib. • Dexamethasone significantly increased the total levels of sunitinib and its metabolite. [ABSTRACT FROM AUTHOR]

The adsorption of pyrazinamide (PZA) drug by the assistance of FeC 20 , FeC 19 , and FeC 18 iron-decorated metallofullerenes were analyzed using density functional theory (DFT) calculations regarding the drug delivery developmental issues. Formations of PZA@FeC 20 , PZA@FeC 19 , and PZA@FeC 18 conjugated systems were analyzed by the structural and electronic features. Meaningful adsorption strengths were found for the models with a priority of PZA@FeC 20 conjugation formation with an exterior iron atom of the metallofullerene. Three configurations were found for each conjugation mainly along with the existence of O...Fe and O...N interactions and a complementary H...C interaction. Hence, the conjugated systems could show a suitable "recovery time" for providing the sensing function along with the changes of "conductance rate" levels. Indeed, the results indicated the formation of observable conjugated systems, in which the conjugations and configurations could be employed regarding a customization towards the drug delivery of PZA antibiotic in a smart mode. [ABSTRACT FROM AUTHOR]

• Chemical and biological characteristics of proteins and polyphenols result in changes in the properties of each other as well as health functionality. • Polyphenols-protein complexes cause the poor function of digestive enzymes. • tea consumption may interfere with the oral bioavailability or activity of some drugs through CYPs inhibition. Biological active compounds in tea such as phenolic compounds have become a focus of research due to their health-beneficial impacts on the human body as well as disease prevention. Moreover, these substances also have beneficial functions as they work as food preservatives. Polyphenols are known to form a complex with protein molecules leading to change in several properties. In this review, the effect of protein-polyphenol interaction on the structure, functionality, nutritional and digestive system as well as the inhibition activity of cytochrome 450 (CYP450) and drug interaction were described. Also, the chemical bonding, which discovered leading to precipitation and changes of protein structure were explained. The feasibility of proteins-polyphenols interaction cause associated with the ability on the digestive system whether enhance the enzymatic activity for digestion or a negative effect of the enzyme inhibition activity. As the bioactive compounds attracting consumer attention in recent years and they do not provide only an advantage side, therefore, it should be significantly studied what impacts to the human body these substances include which are helpful for further investigation. [ABSTRACT FROM AUTHOR]

Background: The advisory system SmartPilot® View (Drägerwerk AG, Lübeck, Germany) provides real-time, demographically adjusted pharmacodynamic information throughout anaesthesia, including time course of effect-site concentrations of administered drugs and a measure of potency of the combined drug effect termed the "'Noxious Stimulation Response Index' (NSRI). This dual-centre, prospective, observational study assesses whether the availability of SmartPilot® View alters the behaviour of anaesthetic drug titration of anaesthetists and improves the Anaesthesia Quality Score (AQS; percentage of time spent with MAP 60-80 mm Hg and Bispectral Index [BIS] 40-60 [blinded]).Methods: We recruited 493 patients scheduled for elective surgery in two university centres. A control group (CONTROL; n=170) was enrolled to observe drug titration in current practice. Thereafter, an intervention group was enrolled, for which SmartPilot® View was made available to optimise drug titration (SPV; n=188). The AQS, haemodynamic and hypnotic effects, recovery times, pain scores, and other parameters were compared between groups.Results: There were 358 patients eligible for analysis. Anaesthesia quality score was similar between CONTROL and SPV (median AQS [Q1-Q3]) 25.3% [7.4-41.5%] and 22.2% [8.0-44.4%], respectively; P=0.898). Compared with CONTROL, SPV patients had less severe hypotension and hypertension, less BIS <40, faster tracheal extubation, and lower early postoperative pain scores.Conclusions: Adding SmartPilot® View information did not affect average drug titration behaviour. However, small improvements in control of MAP and BIS and early recovery suggest improved titration for some patients without increasing the risk of overdosing or underdosing.Clinical Trial Registration: NCT01467167. [ABSTRACT FROM AUTHOR]

Copyright of Actualités Pharmaceutiques is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Adsorption of Thiamazole (TZOL, a medication to treat hyperthyroidism) on the transition metal (TM) doped fullerenes (MF) is investigated to gain insight into the potential development of a smart drug delivery platform. In this computational study, molecular models of adsorbed TZOL on TM-doped and undoped fullerenes were optimized and their structural and electronic features were evaluated using density functional theory (DFT) and the quantum theory of atoms in molecules (QTAIM). The TM-doped models were created by substituting a carbon atom of the original fullerene (F) with a metal atom of the first row of transition metals, yielding ten different MF models. TZOL adsorbate (TZOL@MF) showed stronger interaction through its sulphur group binding to the doped metal in comparison to the original carbon fullerene, i.e. TZOL@F. Our calculations indicate that the most stable conjugate system was TZOL on the vanadium-doped fullerene (TZOL@VF) with a free energy of −37.78 kcal/mol followed by Mn-doped fullerene (−36.86 kcal/mol) while that of all undoped fullerene is −9.18 kcal/mol. The impact of water on the stability of TZOL@MFs was investigated and results show that aqueous phases are even more stable than the gaseous phase, again, with TZOL@VF being the most stable of the conjugate adsorbate/adsorbent pair. Frontier molecular orbital analysis showed significant changes of electronic environment from the MF adsorbent to the TZOL@MF conjugated models. HOMO and LUMO levels and their gap energy detected the variations of electronic environment upon adsorption of TZOL, making this system a potential drug delivery platform capable of detection of loaded and released drug molecules. [ABSTRACT FROM AUTHOR]

This study aimed to provide an understanding of the influence of eugenol on CYP1A2, 2C9, 2D6, and 3A4 in human liver microsomes (HLM). Specific substrate for CYP1A2, 2C9, 2D6, and 3A4 were incubated in HLM with or without eugenol. The formation of their respective metabolites was assessed with HPLC analytical methods. Eugenol at 1, 10 and 100 µM levels inhibited the activity of CYP1A2 and CYP2C9 by 23.38 %, 23.57 %, 39.80 % and 62.82 %, 63.27 %, 67.70 % respectively. While, CYP2D6 and CYP3A4 activity was decreased by 40.70 %, 45.88 %, 62.68 % and 37.41 %, 42.58 % and 67.86 % at 1, 10 and 100 µM eugenol level respectively. The IC 50 value of eugenol for CYP2D6 and CYP3A4 was calculated as 11.09 ± 3.49 µM and 13.48 ± 3.86 µM respectively. Potential herb-drug interactions was noted when eugenol is administered simultaneously with medications metabolized by these enzymes, most notably CYP2C9, CYP2D6 and CYP3A4. [ABSTRACT FROM AUTHOR]

L'allongement de l'intervalle QT expose le patient à des tachycardies ventriculaires pouvant prendre la forme de torsades de pointe potentiellement mortelles. Il est rarement lié à une maladie génétique, plus souvent à la prise de médicaments. Les facteurs de risque associés doivent être connus. Les antidépresseurs et les antiarythmiques sont le plus souvent impliqués. Les personnes âgées doivent être surveillées attentivement. QT interval prolongation exposes the patient to ventricular tachycardias that can take the form of potentially fatal torsades de pointe. It is rarely related to a genetic disease, more often to medication. Associated risk factors should be known. Antidepressants and antiarrhythmics are most often involved. Elderly people should be carefully monitored. [ABSTRACT FROM AUTHOR]

The burden of morbidity and mortality from SARS-CoV-2 infection is especially significant in heart transplant patients who are at higher risk for poor outcomes owing to immunosuppression, blunted response to vaccination, and multiple comorbid conditions. Over the last 3 years the therapeutic landscape for COVID-19 has evolved and our drug armamentaria continues to expand. With these advancements comes a time of great hope to mitigate significant illness from SARS – CoV – 2 infection. However, as with many emerging frontiers, the administration of novel therapeutics to a complex patient population remains challenging. We present a patient case encountered at our institution that highlights the need for increased awareness of nuances while managing COVID-19 infection in a heart transplant recipient. [ABSTRACT FROM AUTHOR]

Mixing alcohol (ethanol) with caffeinated beverages continues to be a common and risky practice. Energy drinks are one type of caffeinated beverage that may be especially problematic when used as mixers, due to their relatively high caffeine content in combination with their highly sweetened flavor profile. The present study used a mouse model of limited-access drinking and lickometer circuitry to examine the effects of an energy drink anid its caffeine content on ethanol consumption. Predictably, the highly sweetened energy drink significantly increased ethanol intake compared to a plain ethanol solution (6.34 ± 0.2 vs. 5.01 ± 0.3 g/kg; Cohen's d = 1.79). Interestingly, adulterating a plain ethanol solution with the same concentration of caffeine (without sweetener) found in the energy drink also increased ethanol intake (5.47 ± 0.3 vs. 4.11 ± 0.3 g/kg; Cohen's d = 1.4). A lower concentration of caffeine was without effect on ethanol drinking. Interestingly, plain caffeine solutions at both tested concentrations provoked high numbers of bottle contacts, indicating that the mice found the solution palatable. These findings suggest that altering the bitterness profile of an ethanol solution with the addition of caffeine can increase intake in a similar manner as sweetening the solution. Further, the findings underscore the importance of taste in motivating ethanol consumption and the potential role that caffeine can have in this process. [ABSTRACT FROM AUTHOR]

• Multicentre retrospective clinical data modelling enables feasible recommendations of antibiotic combinations. • Machine learning is used to construct the ACRM for antibiotic combinations. • The antibiotic combinations recommendation level for ACRM and the risk of drug interactions are positively correlated. With increasing antibiotic resistance and regulation, the issue of antibiotic combination has been emphasised. However, antibiotic combination prescribing lacks a rapid identification of feasibility, while its risk of drug interactions is unclear. We conducted statistical descriptions on 16 101 antibiotic coprescriptions for inpatients with bacterial infections from 2015 to 2023. By integrating the frequency and effectiveness of prescriptions, we formulated recommendations for the feasibility of antibiotic combinations. Initially, a machine learning algorithm was utilised to optimise grading thresholds and habits for antibiotic combinations. A feedforward neural network (FNN) algorithm was employed to develop antibiotic combination recommendation model (ACRM). To enhance interpretability, we combined sequential methods and DrugBank to explore the correlation between antibiotic combinations and drug interactions. A total of 55 antibiotics, covering 657 empirical clinical antibiotic combinations were used for ACRM construction. Model performance on the test dataset showed AUROCs of 0.589–0.895 for various antibiotic recommendation classes. The ACRM showed satisfactory clinical relevance with 61.54–73.33% prediction accuracy in a new independent retrospective cohort. Antibiotic interaction detection showed that the risk of drug interactions was 29.2% for strongly recommended and 43.5% for not recommended. A positive correlation was identified between the level of clinical recommendation and the risk of drug interactions. Machine learning modelling of retrospective antibiotic prescriptions habits has the potential to predict antibiotic combination recommendations. The ACRM plays a supporting role in reducing the incidence of drug interactions. Clinicians are encouraged to adopt such systems to improve the management of antibiotic usage and medication safety. [ABSTRACT FROM AUTHOR]

Monteverdia ilicifolia (Maytenus ilicifolia , Celastraceae), known as "espinheira-santa", has been widely used in Brazil to manage mainly gastrointestinal diseases. This species has been listed in the Brazilian Pharmacopeia and in the National List of Essential Medicines (RENAME). Considering that clinical studies about M. ilicifolia are rare, our group has been performing a broader project designed to evaluate the efficacy of M. ilicifolia capsules in a clinical trial, for this reason, approaches to provide safety to those patients are relevant. We aimed to investigate the potential pharmacokinetic interaction and hepatotoxicity and intestinal toxicity of an aqueous extract of M. ilicifolia and its main phytocompounds, catequin, epicatequin, and quercetin. Slices of liver and intestine of Wistar rats were incubated with different concentrations of M. ilicifolia extract or isolated compounds (catechin, epicatechin and quercetin). Commercial kits were used to evaluate enzyme activities of CYP2D6 and CYP3A4 isoforms, as well as cell viability (MTT) assay and intracellular enzymes leakage, specifically lactate dehydrogenase (LDH), alkaline phosphatase (AP), aspartate aminotransferase (AST), alanine aminotransferase (ALT) were studied. Incubation with M. ilicifolia extract, catechin, epicatechin and quercetin did not affect significantly any evaluated parameter in intestines. The intracellular enzymes leakages, CYP2D6, LDH and AST, were increased with M. ilicifolia extract and quercetin in liver slices. Our in vitro findings highlighted, for the first time, the potential hepatotoxicity induced by an aqueous extract of M. ilicifolia , consequently this species and its products should be avoided in liver diseases, supporting that studies of safety must be performed including in the context of traditional medicinal plants. [Display omitted] • Monteverdia ilicifolia is traditionally used for managing gastric diseases. • M. ilicifolia extract altered liver damage parameters. • In vitro evaluation suggested a potential hepatotoxicity of M. ilicifolia. [ABSTRACT FROM AUTHOR]

Limited guidance is available to assist practitioners in managing complex human immunodeficiency virus (HIV) related pharmacotherapy. Management recommendations of oral anticoagulation (warfarin and direct oral anticoagulants [DOACs]) and highly active antiretroviral therapy (HAART) based on drug-drug interactions (DDI) studies and pharmacokinetic (PK) data are provided. Search of PubMed, EMBASE, and Google Scholar (01/1985 to 12/2018) using the terms "HIV," "DDI," and names of HAART. PK information and DDI screening were obtained from medication package inserts and drug information resources: Micromedex, Lexicomp, HIV-DDI Checker- University of Liverpool. All English literature on DDI or PK interactions was considered for inclusion. In the absence of data, PK principles were used to predict the likelihood of interactions. No clinically significant DDI are expected to occur between DOACs and nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), maraviroc, enfuvirtide, or integrase strand inhibitors (INSTIs) that do not include a pharmacologic booster. Potent cytochrome P (CYP) 450 enzyme inhibition by protease inhibitors (PIs) or pharmacologic boosters may lead to higher concentrations of the DOAC and potentially increase the risk of bleeding. CYP450 enzyme induction by non-nucleoside reverse transcriptase inhibitors (NNRTIs) may lower concentrations of DOACs, which may lead to treatment failure. Warfarin DDIs are variable, therefore close monitoring of the INR is recommended. The potential for DDIs between HAART and oral anticoagulation exists based on PK profiles. Management of these interactions should involve careful selection based on patient characteristics and HAART and anticoagulants with a low potential for DDI should be selected. • No clinically significant DDI between DOACs andNRTIs, maraviroc, enfuvirtide, or INSTIs that do not include a pharmacologic booster. • Potent CYP450 inhibition by PIs or pharmacologic boosters may lead to higher concentrations of the DOAC and potentially increase the risk of bleeding. • CYP450 enzyme induction by NNRTIs may lower concentrations of DOACs, which may lead to treatment failure. [ABSTRACT FROM AUTHOR]

Le devenir des médicaments dans l'organisme fait intervenir divers processus dont la diffusion passive et le transport membranaire. Des protéines de transport participent à l'influx ou à l'efflux cellulaire des molécules. La glycoprotéine P fait partie des pompes d'efflux ayant été les plus étudiées. Drug transport through biological barriers involves various processes including passive diffusion and membrane transport. Transport proteins can be divided into influx or efflux transporters. The P-glycoprotein is one of the most studied efflux pump. [ABSTRACT FROM AUTHOR]

• Highly effective modulator treatment results in improvement in clinical outcomes. • Modulator use may result in drug interactions that need to be managed. • Tacrolimus and modulator use together is manageable. The CFTR modulator combination elexacaftor/tezacaftor/ivacaftor (ETI) is a genetic mutation-targeted treatment in cystic fibrosis that results in profound improvements in clinical outcomes. Each of the compounds are substrates of CYP3A4/5, the cytochrome P450 enzyme family for which tacrolimus is also a substrate. The use of these compounds in an individual with a solid organ transplant has not been previously studied and there is potential for a drug interaction. In this report, we describe a pediatric liver transplant recipient with clinical decline related to cystic fibrosis who improved substantially with ETI, without significant impact on the systemic exposure of either ETI or tacrolimus. [ABSTRACT FROM AUTHOR]

Objective: Rifampin is known to influence the pharmacokinetics of tofacitinib owing to drug interactions. The aim of this study was to determine the efficacy of tofacitinib on co-administration with rifampin in rheumatoid arthritis (RA) patients.Methods: Biologic-naïve RA patients treated with tofacitinib were selected, and electronic medical reports were reviewed retrospectively. All patients underwent screening for latent tuberculosis infection (LTBI) before starting tofacitinib, and patients with positive results were treated to prevent progression to active tuberculosis. To evaluate the efficacy of tofacitinib with or without rifampin, the discontinuation rates of tofacitinib were examined during the first 6 months. Kaplan-Meier analysis was used to construct cumulative discontinuation curves, and comparisons were performed using the log-rank test.Results: Among 81 patients who starting tofacitinib, 21 were LTBI-positive and 18 were administered rifampin concomitantly with tofacitinib. Additionally, 14 of the 81 patients (17.3%) discontinued tofacitinib during the follow-up, and 7 patients discontinued tofacitinib because of uncontrolled RA activity. The discontinuation rates of tofacitinib within the first 6 months were significantly higher in patients treated with rifampin for LTBI than in those not treated with rifampin (lack of efficacy: 24.7% vs. 5.1%, P<0.01; all causes: 38.9% vs. 11.2%, P<0.01).Conclusions: Discontinuation rates were higher in RA patients who started tofacitinib during chemoprophylaxis involving rifampin than in those who did not receive rifampin. Physicians should be aware that the efficacy of tofacitinib could be decreased by chemoprophylactic regimens for tuberculosis. [ABSTRACT FROM AUTHOR]

Direct oral anticoagulants (DOACs) have emerged as safe and effective alternatives to Vitamin-K antagonists for treatment and prevention of arterial and venous thrombosis. Due to their novelty, pharmacokinetic DOAC drug-drug interactions (DDIs) that result in clinical adverse events have not been well-documented. This study aims to systematically review reported pharmacokinetic DDIs resulting in clinical adverse events through documented observational evidence to better inform clinicians in clinical practice. A comprehensive literature review of EMBASE, MEDLINE, and Ovid HealthStar was conducted through March 10th, 2020. Two independent reviewers screened and extracted data from eligible articles according to pre-established inclusion and exclusion criteria. Articles reporting bleeding or thrombotic outcomes in non-controlled (observational) settings resulting from suggested pharmacokinetic DOAC DDIs were included. A total of 5567 citations were reviewed, of which 24 were included following data extraction. The majority were case reports (n = 21) documenting a single adverse event resulting from a suspected DOAC DDI, while the remaining papers were a case series (n = 1) and cohort studies (n = 2). The most commonly reported interacting drugs were amiodarone and ritonavir (bleeding), and phenobarbital, phenytoin, and carbamazepine (thrombosis). Bleeding events more often resulted from a combined mechanism (P-glycoprotein AND CYP3A4 inhibition), whereas thrombotic events resulted from either combined OR single P-glycoprotein/CYP3A4 induction. Current literature evaluating the real-world risk of DOAC DDIs is limited to few case reports and retrospective observational analyses. Clinicians are encouraged to continue to report suspected drug interactions resulting in adverse events. • Patients on direct oral anticoagulants (DOACs) can encounter drug interactions. • Drug interactions can alter the amount of DOAC in a patient's system. • Research on DOAC interactions is currently limited and larger studies are required. • Health providers should continue to be cautious with potential DOAC interactions. [ABSTRACT FROM AUTHOR]

The use of complementary and alternative medicine including herbal medicine (phytotherapy), vitamins, minerals and food supplements is frequent among people living with HIV/AIDS (PLWHAs) who take antiretroviral (ARV) drugs, but is often not known by their prescribing physicians. Some drug–supplement combinations may result in clinically meaningful interactions. In this literature review, we aimed to investigate the evidence for complementary and alternative medicine interactions with ARVs. A bibliographic search of all in vitro , human studies and case reports of the PubMed database was performed to assess the risk of interactions between complementary and alternative self-medication products and ARVs. The 'HIV drug interaction' (https://www.hiv-druginteractions.org) and 'Natural medicines comprehensive database' (https://naturalmedicines.therapeuticresearch.com) interaction checkers were also analysed. St John's wort, some forms of garlic, grapefruit and red rice yeast are known to have significant interaction and thus should not be co-administered, or should be used with caution with certain ARV classes. Data on other plant-based supplements come from in vitro studies or very small size in vivo studies and are thus insufficient to conclude the real in vivo impact in case of concomitant administration with ARVs. Some polyvalent minerals such as calcium, magnesium, and iron salts can reduce the absorption of integrase inhibitors by chelation. Potential interactions with vitamin C and quercetin with some ARVs should be noted and efficacy and tolerance of the treatment should be monitored. This review shows the importance of screening all PLWHAs for complementary and alternative medicine use to prevent treatment failure or adverse effects related to an interaction with ARVs. Further human studies are warranted to describe the clinical significance of in vitro interactions between numerous complementary and alternative medicine and ARVs. [ABSTRACT FROM AUTHOR]

Background: Mechanistic studies have shown that morphine blunts the antiplatelet effects of oral adenosine diphosphate receptor blockers. However, the clinical relevance of this interaction is controversial.Objectives: This study sought to explore the association between morphine and ischemic events in 5,438 patients treated with concomitant clopidogrel presenting with non-ST-segment elevation acute coronary syndromes (NSTEACS) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome) trial. Patients not treated with clopidogrel (n = 3,462) were used as negative controls.Methods: Endpoints were the composite of death, myocardial infarction (MI), recurrent ischemia, or thrombotic bailout at 96 h (4-way endpoint) and the composite of death or MI at 30 days.Results: In patients treated with clopidogrel, morphine use was associated with higher rates of the 4-way endpoint at 96 h (adjusted odds ratio [OR]: 1.40; 95% confidence interval [CI]: 1.04 to 1.87; p = 0.026). There was a trend for higher rates of death or MI at 30 days (adjusted OR: 1.29; 95% CI: 0.98 to 1.70; p = 0.072), driven by events in the first 48 h (adjusted hazard ratio: 1.54; 95% CI: 1.07 to 2.23; p = 0.021). In patients not treated with clopidogrel, morphine was not associated with either the 4-way endpoint at 96 h (adjusted OR: 1.05; 95% CI: 0.74 to 1.49; p = 0.79; pinteraction = 0.36 ) or death or MI at 30 days (adjusted OR: 1.07; 95% CI: 0.77 to 1.48; p = 0.70; pinteraction = 0.46).Conclusions: When used concomitantly with clopidogrel pre-treatment, morphine was associated with higher rates of ischemic events in patients with NSTEACS. (EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome; NCT00089895). [ABSTRACT FROM AUTHOR]

It is known that potent inhibition of organic-anion-transporting polypeptide (OATP)1B1 increases exposure to statins, leading to severe adverse effects. The aim of this study was to propose a parameter and its criteria in OATP1B1 inhibition assay at the early drug discovery stage to avoid compounds with the risk of statin-related adverse effects. According to drug label information, most compounds classified as "contraindicated" or "should be avoided" when administered concomitantly with statins increased their AUCs more than 4-fold. Generally, R values where R = 1 + plasma unbound fraction (fu) × maximum inhibitor concentration at the inlet to the liver/IC 50 are used to evaluate the extent of clinical drug interaction. However, clinical doses and C max cannot be determined at the screening stage. Therefore, we estimated the correlations between change in AUC of statins concomitantly administered with OATP1B1 inhibitors and various parameters including fu/IC 50. Cyclosporin A, rifampicin, and telaprevir increased the AUC of statins more than 4-fold and fu/IC 50 of these compounds was >0.1 L/μmol. On the other hand, fu/IC 50 of other compounds was ≤0.03 L/μmol. This study indicates that fu/IC 50 is a useful parameter to avoid compounds that seriously affect statin potency through interaction with OATP1B1 at the screening stage. [ABSTRACT FROM AUTHOR]

Co-use of marijuana and tobacco products is the second most common drug combination among adolescents. Nicotine (NIC) and cannabinoid use during adolescence induce similar detrimental changes, raising the hypothesis that simultaneous exposure could result in even more severe outcomes. Thus, we investigated whether the co-exposure to NIC and the synthetic cannabinoid WIN 55,212–2 (WIN) in adolescent mice causes behavioral outcomes different from those observed after exposure to a single drug. Male Swiss mice were exposed twice daily to NIC, WIN, or NIC + WIN during adolescence (PND28–47) or adulthood (PND70–89). Drug combination led to a greater reduction in weight gain in adolescent mice, while NIC-induced weight loss was observed in adults. During administration, NIC provoked hypothermia, and WIN produced hyperlocomotion in adolescent and adult mice. Animals exposed to NIC + WIN presented a profile of changes similar to those exposed to NIC. After drug exposure, changes in locomotion, thigmotaxis, social preference, prepulse inhibition, and working and recognition memory were evaluated. Adolescent but not adult mice exposed to NIC showed withdrawal-related hyperlocomotion unaffected by WIN co-administration. An age-specific impairment in object recognition memory was induced only by drug co-exposure during adolescence, which resolved spontaneously before reaching early adulthood. A transient decrease in hippocampal α7 nAChR subunit and CB1 receptor mRNA levels was induced by NIC exposure, which may be involved but is not enough to explain the memory impairment. Our work confirms the potential of NIC and cannabinoids association to aggravate some of the individual drug effects during critical neurodevelopmental periods. [Display omitted] • Age of exposure determines the behavioral outcomes of nicotine + WIN 55,212–2. • In adolescent mice, nicotine + WIN 55,212–2 causes short-term memory impairment. • Nicotine withdrawal induces hyperlocomotion not affected by WIN 55,212–2. • In adult mice, nicotine + WIN 55,212–2 does not cause lasting behavioral changes. • Nicotine withdrawal reduces hippocampal α7 nicotinic and CB1 receptor mRNA levels. [ABSTRACT FROM AUTHOR]

L'association d'un inhibiteur du cytochrome P450 (CYP) 3A4 avec une statine entraîne une interaction médicamenteuse. Trois solutions peuvent être envisagées avec le médecin selon les médicaments prescrits : la substitution de l'inhibiteur du CYP3A4, la diminution de la posologie de la statine ou son remplacement par une autre statine n'interagissant pas ou peu avec les inhibiteurs du CYP3A4. The combination of a cytochrome (CYP) 3A4 inhibitor with a statin entails a drug interaction. Three solutions can be considered together with the doctor according to the prescribed drugs: substitution of the CYP3A4 inhibitor, reduction in the dosage of the statin or its replacement by another statin that interacts little or not at all with CYP3A4 inhibitors. [ABSTRACT FROM AUTHOR]

Les équipes officinales délivrent souvent des conseils pour se prémunir des morsures de tiques. Dans le cadre du traitement de la maladie de Lyme, ils dispensent aussi des ordonnances aux personnes en ayant été victimes. Il faut alors vérifier l'absence de risque d'interaction médicamenteuse. Pharmacy teams often provide advice on how to prevent tick bites. As part of the treatment of Lyme disease, they also dispense prescriptions to people who have suffered from it. It is then necessary to verify the absence of risk of drug interaction. [ABSTRACT FROM AUTHOR]

In the United States, the evolving landscape of state-legal marijuana use for recreational and/or medical purposes has given rise to flourishing markets for marijuana and derivative products. The popularity of these products highlights the relative absence of safety, pharmacokinetic, and drug interaction data for marijuana and its constituents, most notably the cannabinoids. This review articulates current issues surrounding marijuana terminology, taxonomy, and dosing; summarizes cannabinoid pharmacology and pharmacokinetics; and assesses the drug interaction risks associated with co-consuming marijuana with conventional medications. Existing pharmacokinetic data are currently insufficient to fully characterize potential drug interactions precipitated by marijuana constituents. As such, increasing awareness among researchers, clinicians, and federal agencies regarding the need to conduct well-designed in vitro and clinical studies is imperative. Mechanisms that help researchers navigate the legal and regulatory barriers to conducting these studies would promote rigorous evaluation of potential marijuana-drug interactions and inform health care providers and consumers about the possible risks of co-consuming marijuana products with conventional medications. [ABSTRACT FROM AUTHOR]

Ertugliflozin (ERTU) is a novel, potent, and highly selective sodium glucose cotransporter 2 inhibitor that has been recently approved for the treatment of type 2 diabetes mellitus. We describe a novel bioanalytical method using high-performance liquid chromatography (HPLC) coupled with fluorescence detection for quantitative determination of ERTU in rat plasma. Acetonitrile-based protein precipitation method was used for sample preparation, and chromatographic separation was performed on a Kinetex® C18 column with an isocratic mobile phase comprising acetonitrile and 10 mM potassium phosphate buffer (pH 6.0). The eluent was monitored by a fluorescence detector at an optimized excitation/emission wavelength pair of 277/320 nm. The method was validated to demonstrate the selectivity, linearity (ranging from 4 to 2000 ng/mL), precision, accuracy, recovery, matrix effect, and stability in line with the current FDA guidelines. The newly developed method was successfully applied to investigate the pharmacokinetic interactions of ERTU with mefenamic acid (MEF) and ketoconazole (KET). The findings of the present study revealed that the pharmacokinetics of ERTU may be altered by concurrent administration of MEF and KET in rats. To our knowledge, the present study is the first to develop a validated bioanalytical method for quantification of ERTU using HPLC coupled with fluorescence detection and to assess the drug interaction potential of ERTU with non-steroidal anti-inflammatory (MEF) and azole antifungal (KET) drugs. • A novel bioanalytical method for ERTU using HPLC with fluorescence detection • The method offers sufficient sensitivity comparable to the reported LC-MS/MS methods. • The method was validated and applied to drug–drug interaction study in rats. • The PK of ERTU was significantly altered by concurrent administration of KET. • The PK of ERTU was considerably (up to 38.2%, but insignificantly) affected by MEF. [ABSTRACT FROM AUTHOR]

Background: Some medications are more rapidly metabolized by smokers; upon smoking cessation, medication metabolism may be significantly reduced, resulting in medication-related adverse events. Clozapine, olanzapine and theophylline have been deemed to have potentially highly significant interactions with smoking cessation, which could lead to seizures, extrapyramidal effects and tachycardia, respectively. This study examined the period prevalence and characteristics of patients at risk of highly significant medication-smoking cessation interactions when admitted to a smoke-free hospital.Methods: A retrospective cross-sectional study was undertaken in an Australian tertiary-referral hospital with a well-established electronic prescribing system. Smokers prescribed clozapine, olanzapine or theophylline prior to and during a hospital admission in 2015 were included. Length of hospital stay, daily doses, and recognition of the potential interaction by treating clinicians were determined from medical records.Results: The period prevalence of patients at risk of a potentially highly significant medication-smoking cessation interaction was 23/48 (48%), 66/256 (26%) and 1/16 (6%) amongst smokers prescribed clozapine, olanzapine or theophylline, respectively. These interactions were poorly recognized by healthcare professionals during the admission.Conclusions: Up to one in two patients receiving medications that have potentially highly significant interactions with smoking cessation may be experiencing clinically significant potential interactions. Such interactions, however, were commonly overlooked by hospital staff. Interventions to improve awareness of this issue are warranted. [ABSTRACT FROM AUTHOR]

Abstract A continuous effort has been given to find out a new drug that is effective against tuberculosis (TB) from both susceptible and resistant strains of Mycobacterium tuberculosis. Bedaquiline represents a recently approved anti-TB drug, which has a unique mechanism of action to fight against multi drug resistance (MDR). Some severe side effects and drug-drug interactions are associated with the treatment of bedaquiline. Moreover, World Health Organisation (WHO) has also been provided guidelines in the year of 2013 for the use of bedaquiline and encourages additional investigation into it. Hence, the pharmacokinetics of bedaquiline upon coadministration with the drug has to be explored in the preclinical model and for which a liquid chromatography tandem mass spectrometry (LC-MS/MS) based bioanalytical method for quantitation of bedaquiline will be useful. A simple, sensitive and rapid LC-MS/MS method was developed, validated and successfully applied to drug interactions of bedaquiline upon coadministration with cytochrome P450 3A4 (CYP3A4) inducers/inhibitors orally in Wistar rats. Results reveal that ciprofloxacin and fluconazole have marked effect to hinder the pharmacokinetics of bedaquiline but isoniazid, verapamil and carbamazepine have no significant effect on bedaquiline pharmacokinetics. Overall, this new bioanalytical method for estimation of bedaquiline in rat plasma was found to be helpful to assess the pharmacokinetics of bedaquiline and very much useful for evaluation of preclinical drug-drug interaction before considering costly and perilous clinical exploration. Highlights • LC-MS/MS method for quantification of bedaquiline (TMC207) in rat plasma • Suitable method for preclinical studies as requires only 10 μL plasma • Highly sensitive bioanalytical method to quantitate very low level of bedaquiline • Useful method to assess preclinical drug interaction of such a recent anti-TB drug [ABSTRACT FROM AUTHOR]

Résumé Le syndrome de Cushing est le plus souvent d'origine iatrogénique, dû à la prise au long cours de glucocorticoïdes ou l'administration d'un traitement associant un glucocorticoïde et des médicaments modifiant la pharmacocinétique de celui-ci. Les professionnels de santé doivent demeurer vigilants lors de la délivrance et du suivi médicamenteux. Summary Cushing's syndrome is in most cases iatrogenic in origin, due to the prolonged intake of glucocorticoids or the administration of a treatment combining a glucocorticoid and medicines altering its pharmacokinetics. Health professionals must remain vigilant when dispensing medicines and monitoring their intake. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to analyze the extent of co-medication and to assess potential interactions between antiepileptic drugs (AEDs) and other drugs among patients with epilepsy.Methods: We studied 663 consecutive patients with epilepsy seen in tertiary outpatient clinic. Data on epilepsy and current treatment with AED(s) were collected from structured interview and medical records. Other medications used regularly were classified according to the Anatomical Therapeutic Chemical classification system. Possible drug interactions between AEDs and other drugs were analyzed with the use of IBM Micromedex® database.Results: Studied sample included 395 women; 54.5% of subjects were on monotherapy. Enzyme-inducing AED(s) were used by 127 patients (19.2%). Among 265 patients who used medications other than AEDs (40.0% of all subjects), potential major and moderate interactions between AEDs and other drugs were found in 80 patients (30.1%). Most prevalent major interactions included: ethinylestradiol/estradiol - valproate/oxcarbazepine/carbamazepine, sertraline-carbamazepine, and simvastatin-carbamazepine. A total number of currently used medications (OR = 1.26 [1.07-1.48] per one additional medication; p = 0.005) and the use of enzyme-inducing AEDs (OR = 2.78 [1.51-5.12]; p < 0.001) were independent predictors of interactions between AEDs and other drugs.Conclusions: Co-medication is common (40%) among patients with epilepsy. Potential major or moderate interactions between AED(s) and other drugs are noted in 30.1% of patients exposed to at least one medication other than AED (12.1% of the entire cohort). The risk of potential interactions increases with the number of medications used chronically and with the use of hepatic enzyme-inducing AEDs. [ABSTRACT FROM AUTHOR]

Abstract A combination of antiplatelet drugs with high-intensity statin therapy is a standard in patients with coronary events. Concomitant treatment with ticagrelor, a moderate CYP3A4 inhibitor, and CYP3A4-metabolized statins such as atorvastatin, might lead to an increased risk of muscle-related adverse events. Therefore, investigation of concentrations of these compounds in clinical samples is necessary. For this purpose, an LC-MS/MS method was developed for simultaneous determination of ticagrelor and its active metabolite (AR-C124910XX), as well as 2-hydroxyatorvastatin, which is the main metabolite of atorvastatin. Protein precipitation was used for sample preparation and afterwards the analytes were separated on a Kinetex XB-C18 column with an isocratic elution (water and acetonitrile with 0.1% formic acid, 57:43, v/v). Detection was performed on a triple-quadrupole MS with multiple-reaction-monitoring via electrospray ionization. The method was fully validated according to the EMA's recommendations. Determination was possible within ranges: 1.25–2000 ng/mL for ticagrelor, 1.25–1000 ng/mL for its AR-C124910XX, 1.25–50 ng/mL for atorvastatin and 1.14–45.73 for 2-hydroxyatorvastatin. Within and between-run accuracy, expressed as a relative error, was within 0.05–10.56% for all analytes, while within and between-run precision, expressed as coefficient of variation, was within 0.61–9.91%. Ticagrelor, atorvastatin and their main metabolites were found to be stable in acetonitrile stock solutions, and in plasma samples stored for 24 h at room temperature, 1 month at −25 °C, after 3 cycles of freezing and thawing, and in processed samples stored as a dry residue for 24 h at 4 °C and for 24 h in autosampler at room temperature. This simple and rapid method allowed simultaneous determination of the analytes for the first time. The procedure was applied for the pharmacokinetic study of ticagrelor, its active metabolite AR-C124910XX, and 2-hydroxyatorvastatin in patients simultaneously treated with ticagrelor and atorvastatin. Highlights • Determination of ticagrelor, atorvastatin and their metabolites in plasma • Simultaneous and rapid quantitative analysis within a single run • The LC-MS/MS method was applied for the analysis of clinical samples. [ABSTRACT FROM AUTHOR]

Résumé L'apparition de combinaisons d'antiviraux à action directe a métamorphosé la prise en charge de l'hépatite C. Si leur prescription reste hospitalière et réservée aux spécialistes, leur mise à disposition en double circuit pharmaceutique renforce le rôle du pharmacien en matière d'observance, de prévention des effets indésirables et de détection des interactions médicamenteuses. Le remboursement à 100 % favorise l'accès de toutes les populations au traitement. Summary The emergence of combinations of direct-acting antivirals has revolutionized the paradigm of hepatitis C treatment. Although those combinations are still prescribed by hospital based specialists, they have been made available in both hospital and community pharmacies. The pharmacist role has been reinforced in terms of managing compliance of the patients, prevention of adverse effects and drug interactions detection. The full reimbursement for all populations favours a wide access to the treatment. [ABSTRACT FROM AUTHOR]

Abstract Objectives To compare the in vitro interactions between tacrolimus (TAC)/triamcinolone acetonide (TRI) with itraconazole (ITC), terbinafine (TRB), bifonazole (BIZ), and amorolfine (AMF) in 28 clinical dermatophyte isolates, including 13 Trichophyton rubrum , 6 Trichophyton mentagrophytes , 5 Microsporum canis , and 4 Epidermophyton floccosum strains. Materials and methods The interactions between TAC or TRI with antifungal agents were tested according to the microdilution checkerboard technique adapted from the CLSI M38-A2 microdilution method. Results TAC and TRI did not exhibit significant antifungal activity against the tested strains at the highest concentration (MICs > 8 μg/mL). However, a strong synergistic interaction was observed for combinations of TAC with ITC (53%), TRB (53%), or BIZ (63%) against Trichophyton strains. Comparatively, TRI/ITC (11%) and TRI/BIZ (16%) combinations showed weaker synergistic activity against the same Trichophyton strains. TAC also showed synergistic interaction with ITC against 20% M. canis strains, with TRB against 60% M. canis strains, and with BIZ against 25% E. floccosum strains. No synergism was observed when M. canis and E. floccosum strains were exposed to TRI in combination with these drugs. Antagonism was not observed for any combinations. Conclusions Compared with TRI, TAC showed better synergy when combined with antifungal agents, especially topical TRB and BIZ, against dermatophyte isolates. [ABSTRACT FROM AUTHOR]

La mise en place d'un traitement antihypertenseur de type inhibiteur de l'enzyme de conversion chez un patient traité par sels de lithium peut entraîner un déséquilibre de la lithiémie. Les mécanismes cellulaires d'augmentation de la lithiémie comprennent notamment une hausse de la réabsorption du lithium. Le pharmacien d'officine doit savoir quelle conduite adopter face à une telle interaction. The introduction of an antihypertensive treatment such as a converting enzyme inhibitor in a patient treated with lithium salts can lead to an imbalance in lithiemia. Cellular mechanisms of increased lithiemia include increased lithium reabsorption. The dispensing pharmacist needs to know how to deal with such an interaction. [ABSTRACT FROM AUTHOR]

FMS-like tyrosine kinase 3 (FLT3) mutations occur in almost 30% of acute myeloid leukemia (AML) patients. Despite the initial clinical efficacy of FLT3 inhibitors, many treated AML patients with mutated FLT3 eventually relapse. This review critically discusses the opportunities and challenges of FLT3-targeted therapies and sheds light on their drug interactions as well as potential biomarkers. Furthermore, we focus on the molecular mechanisms underlying the resistance of FLT3 internal tandem duplication (FLT3-ITD) AMLs to FLT3 inhibitors alongside novel therapeutic strategies to reverse resistance. Notably, dynamic heterogeneous patterns of clonal selection and evolution contribute to the resistance of FLT3-ITD AMLs to FLT3 inhibitors. Ongoing preclinical research and clinical trials are actively directed towards devising rational "personalized" or "patient-tailored" combinatorial therapeutic regimens to effectively treat patients with FLT3 mutated AML. [Display omitted] • Next-generation FLT3 TKIs are less toxic compared to multi-kinase inhibitors. • Most FLT3 TKI treated patients eventually relapse. • Distinct mechanisms contribute to the resistance of type I/II FLT3 TKIs. • Dynamic clonal selection and evolution is evident during FLT3 TKIs therapy. • "One-size-fits-all" combo-regimens are unlikely to effectively work. [ABSTRACT FROM AUTHOR]

• Develop and validate a UPLC-MS/MS method for the identification of vericiguat • Astragaloside IV significantly reduces C max of vericiguat • Drug-drug interaction might happen between vericiguat and astragaloside IV • Astragaloside IV might decrease vericiguat exposure via P-glycoprotein Vericiguat (VER) is a novel soluble guanylate cyclase stimulator treating symptomatic chronic heart failure (HF), and it is a substrate of both transporters P-glycoprotein and breast cancer resistance protein (BCRP). Astragaloside IV (ASIV) is the main active ingredient in Radix Astragali (Huangqi), a traditional Chinese medicine widely used for HF treatment in China. ASIV's effect on the protein expression of P-glycoprotein and BCRP has been observed, its impact on VER metabolism remain uncertain. In the present study, male Sprague-Dawley rats were administered with 20 mg/kg ASIV and 1 mg/kg VER to study their pharmacokinetics. Blood samples were subject to liquid-liquid extraction, and riociguat was employed as the internal standard (IS). The analytical method involved a C18 column (XSelect® HSS T3 column, 2.1 × 100 mm, 2.5 μm) with a mobile phase of 0.1% formic acid and acetonitrile for gradient elution. The flow rate of the mobile phase was set at 0.2 mL/min, and 5 µL of the sample was used for analysis. The positive ion multi-response monitoring mode was utilized with a transition of m/z 427.4→109.1 for VER and m/z 423.3→109.1 for the IS. The method exhibited good linearity within the concentration range of 0.1 to 300 ng/mL (r = 0.9987), and all the validation processes were conducted in accordance with the requirements of biological analysis. The pharmacokinetic results revealed that ASIV did not significantly alter the main parameters of VER, except for C max , which decreased by 33.2% (P < 0.05). Overall, our study successfully established a selective, sensitive and repeatable ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis for detecting VER in rat plasma. [ABSTRACT FROM AUTHOR]

• A fatal overdose of BRONTM, an over-the-counter antitussive, with fluvoxamine was described. • Fluvoxamine, a potent cytochrome P450 (CYP)1A2 inhibitor, may increase blood levels of caffeine, one of the main components of BRONTM. • More attention should be paid to drug-drug interactions. A man in his forties was found dead in his friend's home, with moderate putrefaction. Quantitative toxicological analysis showed that concentrations of caffeine, chlorpheniramine, dihydrocodeine, and methylephedrine were 183.3 µg/mL, 0.533 µg/mL, 2.469 µg/mL and 8.336 µg/mL, respectively. Ephedrine, amitriptyline, nortriptyline, etizolam, fluvoxamine and 7-aminoflunitrazepam were detected in an aortic blood sample. Caffeine, chlorpheniramine, dihydrocodeine and methylephedrine are the main components of BRONTM, an over-the-counter antitussive sold in Japan. Those concentrations in blood were within fatal ranges. Caffeine is classified as a methylxanthine and is mainly metabolized by cytochrome P450 (CYP)1A2. Fluvoxamine is a potent CYP1A2 inhibitor. Blood fluvoxamine concentration was within the therapeutic range, but would have increased blood caffeine level by the inhibition of caffeine metabolism. The conclusion was that his death was caused by BRONTM overdose. Inhibition of caffeine metabolism may increase blood caffeine concentrations. This suggests that more attention should be paid to potential interactions between multiple drugs. [ABSTRACT FROM AUTHOR]

Objective: To explore the pharmacokinetic interaction between isotretinoin, a cytochrome P-450 (CYP) inducer and potent teratogen, and the etonogestrel contraceptive implant.Study Design: We enrolled healthy reproductive-age women initiating isotretinoin and using an etonogestrel implant. We compared serum etonogestrel concentrations at baseline and after four and nine weeks of isotretinoin co-administration using a validated assay.Results: Among eight implant users, all serum etonogestrel concentrations remained >90 pg/mL during isotretinoin co-administration with no significant changes from baseline (p = 0.25, Friedman's test).Conclusion: In this exploratory study, we found that isotretinoin did not cause serum etonogestrel concentrations to fall below the threshold for ovulatory suppression (<90 pg/mL) among implant users.Implications: Reproductive-age women treated with isotretinoin require reliable contraception to prevent pregnancies impacted by teratogenic-effects. This small study demonstrates that contraceptive implant users maintained serum etonogestrel concentrations above the threshold for consistent ovulatory suppression during isotretinoin co-administration. The contraceptive implant remains an appropriate option for patients considering isotretinoin therapy. [ABSTRACT FROM AUTHOR]

Abstract Breast cancer resistance protein (BCRP) is a point of interest in drug-drug interaction safety testing. Therefore, a consensus probe that can be applied as victim in multiple experimental settings is of great benefit. Identification of candidates has been driven by the amount and quality of available clinical data, and as a result, drugs such as sulfasalazine and rosuvastatin have been suggested. In this article, the in vitro performance of 5 possible alternatives was evaluated: atorvastatin, chlorothiazide, dantrolene, topotecan, and teriflunomide, and benchmarked against sulfasalazine and rosuvastatin in reference in vitro assays for BCRP drug-drug interaction testing. Based on the results, teriflunomide is proposed as an alternate in vitro BCRP probe. [ABSTRACT FROM AUTHOR]

Abstract Purpose: Red ginseng is one of the world's most popular herbal medicines; it exhibits a wide range of pharmacologic activities and is often co-ingested with other herbal and conventional medicines. This open-label, randomized, 3-period study investigated the in vivo herb–drug interaction potential for red ginseng extract with cytochrome P-450 (CYP) enzymes and organic anion-transporting polypeptide (OATP) 1B1. Methods: Fifteen healthy male volunteers (22-28 years; 57.1-80.8 kg) were administered a single dose of cocktail probe substrates (caffeine 100 mg, losartan 50 mg, omeprazole 20 mg, dextromethorphan 30 mg, midazolam 2 mg, and pitavastatin 2 mg) and single or multiple doses of red ginseng extract for 15 days. Findings: The pharmacokinetic profiles of the probe substrates and metabolites after single- or multiple-dose administration of red ginseng extracts were comparable to the corresponding profiles of the control group. The geometric mean ratio of AUC 0–t and 90% CIs for the probe substrate drugs between the control and multiple doses of red ginseng for 15 days were within 0.8 to 1.25 (CYP2C9, CYP3A4, and OATP1B1 probe substrates) or slightly higher (CYP1A2, CYP2C19, and CYP2D6 probe substrates). Additional assessments of the in vitro drug interaction potential of red ginseng extracts and the ginsenoside Rb1 on drug-metabolizing enzymes and transporters using human liver microsomes, cryopreserved human hepatocytes, and transporter-overexpressed cells were negative. Implications: Red ginseng poses minimal risks for clinically relevant CYP- or OATP-mediated drug interactions and is well tolerated. Clinical Research Information Service registry no.: [ABSTRACT FROM AUTHOR]