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Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) are metabolized either via carboxylesterase (niraparib) or cytochrome P450 (CYP) enzymes (olaparib and rucaparib). Patients with advanced epithelial ovarian cancer (aOC) who receive concomitant medication metabolized by the CYP system may be at risk of drug-drug interactions impacting PARPi efficacy and tolerability. This study investigated CYP inhibitor/inducer treatment patterns in the first-line maintenance (1Lm) setting for patients with aOC. This retrospective cohort study used de-identified databases of US patients with aOC. Eligible patients were aged ≥18 years, diagnosed with aOC between January 2015-March 2021, and received CYP inhibitors/inducers during 1Lm PARPi initiation or the eligibility window (90 days before to 120 days after first-line platinum-based therapy ended [index]). Patients were either prescribed 1Lm PARPi monotherapy (PARPi cohort) or were not prescribed any 1Lm therapy within 120 days post-index (PARPi-eligible cohort). Strong/moderate CYP inhibitors/inducers were defined as area under the plasma concentration-time curve ratio (AUCR) ≥2 or clearance ratio (CL) ≤0.5 (inhibitors), and AUCR ≤0.5 or CL ratio ≥2 (inducers). Of 1411 patients (median age 63), 158 were prescribed PARPis and 1253 were PARPi-eligible. Among the PARPi cohort, 46.2%, 48.7%, and 5.1% were prescribed niraparib, olaparib, and rucaparib, respectively. For patients prescribed olaparib or rucaparib, 42.4% also received strong and/or moderate CYP inhibitors/inducers. This real-world study indicated a considerable proportion of patients received strong and/or moderate CYP inhibitors/inducers and were prescribed PARPis metabolized by the CYP system. Understanding potential impacts of concomitant CYP inhibitors/inducers on PARPi efficacy and safety is warranted.

Aim: Characterize febrile neutropenia in the real-world and explore potentially modifiable risk factors. Patients & methods: Characteristics of patient presenting with febrile neutropenia after systemic cancer treatment were investigated, with a thorough evaluation of potential risk factors. Results: The rate of febrile neutropenia requiring hospitalization was comparable with clinical trials (mean absolute difference 2%, 95% CI: -1–4%; p = 0.29). The in-hospital mortality rate was 6%. Most cases resulted from low-risk regimens (50%) and 18.2% presented no apparent risk factors. 42.4% of patients presented modifiable factors potentially involved in the occurrence of febrile neutropenia. Conclusion: Febrile neutropenia rate in contemporary real-world evidence is comparable with clinical trials. Appropriate G-CSF administration and avoidance of potentially harmful drug-interactions represent potential areas for improvement. Even with the advance of new cancer treatment strategies, chemotherapy remain an important part of the treatment of many cancer patients. Febrile neutropenia remains one of the most common causes of cancer treatment morbidity and mortality. Other factors may come into play in the occurrence of febrile neutropenia in the real-world setting, compared with the strictly controlled environment of clinical trials. The febrile neutropenia rate in this real-world setting was comparable to rate in clinical trials. Many patients presented a modifiable factor potentially involved in the occurrence of febrile neutropenia, such as an abnormal pre-treatment laboratory value, a potentially significant drug interaction between a comedication and chemotherapy, or not receiving G-CSF in accordance with the guidelines. Despite a thorough review, we found no risk factor for 18 patients (18.2%) treated with low-risk regimen. Despite a thorough evaluation of known risk factors, febrile neutropenia remains difficult to predict for individual patients and presents an opportunity for further study. Appropriate G-CSF administration and avoidance of potentially harmful drug interactions could help reduce the burden of febrile neutropenia. [ABSTRACT FROM AUTHOR]

Studying factors that cause interindividual variability of carboxylesterase 1 (CES1) activity is currently difficult due to limited methods. Here, fluorogenic tools for measuring CES1 activity are developed and demonstrated to report on these factors in living cells. These tools enable experiments that will develop a deeper understanding of CES1 metabolism. [ABSTRACT FROM AUTHOR]

Approximately one-third of Americans use healthcare approaches including herbs and botanicals, such as St. John's wort (SJW), to improve overall well-being, gain control over their health, and manage the adverse reactions of conventional therapies. This article examines the use of SJW in cancer care, discussing its pharmacokinetics, toxicity, and potential interactions with cancer treatments while emphasizing the importance of patient education and collaboration between oncology nurses and pharmacists to ensure safe and effective care. [ABSTRACT FROM AUTHOR]

Accurately predicting drug-target affinity is crucial in expediting the discovery and development of new drugs, which is a complex and risky process. Identifying these interactions not only aids in screening potential compounds but also guides further optimization. To address this, we propose a multi-perspective feature fusion model, MFF-DTA, which integrates chemical structure, biological sequence, and other data to comprehensively capture drug-target affinity features. The MFF-DTA model incorporates multiple feature learning components, each of which is capable of extracting drug molecular features and protein target information, respectively. These components are able to obtain key information from both global and local perspectives. Then, these features from different perspectives are efficiently combined using specific splicing strategies to create a comprehensive representation. Finally, the model uses the fused features to predict drug-target affinity. Comparative experiments show that MFF-DTA performs optimally on the Davis and KIBA data sets. Ablation experiments demonstrate that removing specific components results in the loss of unique information, thus confirming the effectiveness of the MFF-DTA design. Improvements in DTA prediction methods will decrease costs and time in drug development, enhancing industry efficiency and ultimately benefiting patients. • The MFF-DTA model is proposed to accurately predict the affinity relationship between drugs and target proteins. • The model includes multiple feature extractors to capture global and local key features. • We create a comprehensive and information-rich representation. • The model has demonstrated strong performance on public datasets. [ABSTRACT FROM AUTHOR]

This study intended to evaluate the interactions between zamicastat and epoprostenol in healthy human subjects. This was a single‐center, open‐label, two‐period study. In period 1, epoprostenol 8 ng/kg/min was administered alone. In period 2, epoprostenol 8 ng/kg/min was administered following an 8‐day treatment with zamicastat. Since the initial dose of epoprostenol showed to be insufficiently tolerated, it was decreased to 6 ng/kg/min. Blood samples were collected to determine the metabolites of epoprostenol and concentrations of zamicastat and its metabolites. A total of 54 subjects were enrolled and data from 28 subjects were available for pharmacokinetic analysis. The epoprostenol plus zamicastat‐to‐epoprostenol geometric means ratio (GMR) and corresponding 90% confidence interval (CI) for Cav,ss and area under the plasma concentration–time curve from time 0 up to 16 h at steady state (AUC0‐16,ss) of the metabolites of epoprostenol were within the acceptance bioequivalence range (80.00%‐125.00%). The intrasubject coefficient of variation (ISCV) was below 10% for both parameters, on both metabolites. For zamicastat AUC0‐τ,ss, the zamicastat plus epoprostenol‐to‐zamicastat GMR and corresponding 90% CI were within the bioequivalence acceptance range, while for zamicastat Cmax,ss, the lower limit of the 90% CI was slightly below the acceptance range. For zamicastat metabolites, Cmax,ss and AUC0‐τ,ss and the zamicastat plus epoprostenol‐to‐zamicastat GMR were below the acceptance bioequivalence range. ISCV was between 30% and 41% for Cmax,ss and between 21% and 41% for AUC0‐τ,ss, for zamicastat and both metabolites. This study showed that the administration of zamicastat did not significantly modify the cardiovascular effects of epoprostenol and that the interactions between zamicastat and epoprostenol are not expected to be clinically relevant. [ABSTRACT FROM AUTHOR]

Infusion pump-based therapies are an effective treatment option for patients with advanced Parkinson´s disease. Achieving monotherapy with infusion-based therapies could simplify the treatment regimen, provide better medication adherence, reduce adverse events and drug interactions. This review presents the literature data on the efficacy, safety, and achievability of monotherapy with all available infusion-based therapies, including apomorphine, levodopa-carbidopa-intestinal gel (LCIG), levodopa-entacapone-carbidopa intestinal gel (LECIG), and foslevodopa-foscarbidopa (LDp/CDp). In summary, monotherapy is achievable and effective in most patients on intestinal levodopa infusion therapy and in some patients on apomorphine infusion. There is a need for further investigation of monotherapy compared to polytherapy, especially in new pump treatment options (LECIG and LDp/CDp). Future research should reveal which patients on infusion-based therapies could benefit from monotherapy, including identification of potential baseline predictors of achieving monotherapy in patients treated with specific infusion-based therapies. [ABSTRACT FROM AUTHOR]

Salicylates are generally present in plants as part of their defense system against pathogens and environmental stress. Major dietary sources of salicylates were found in spices and herbs, such as curry and paprika (hot powder). Several studies suggest that these natural salicylates offer health benefits in the human body, such as antidiabetic, anticancer, antiviral, and anti-inflammatory properties. However, despite their advantages, salicylates can be harmful to people with allergies, and high doses of salicylates may cause respiratory alkalosis and gastrointestinal bleeding. Additionally, salicylates can interact with certain drugs, such as nonsteroidal anti-inflammatory drugs and warfarin. This narrative review aimed to consolidate recent information on the content of salicylates in food based on the literature, while also highlighting the benefits and risks associated with salicylate consumption in humans. Based on the literature review and analysis of results, it can be concluded that the dietary intake of salicylates in vegetarians can be relatively high, resulting in concentrations of salicylic acid in the blood and urine that are comparable to those observed in patients taking a low dose of aspirin (75 mg). This suggests that a diet rich in salicylates may have potential benefits in preventing and treating some diseases that require low doses of aspirin. [ABSTRACT FROM AUTHOR]

Drug molecules exist as complexed with serum proteins such as human serum albumin (HSA) and/or unbound free form in the blood circulation. Drugs can be effective only when they are free. Thus, it is important to understand aspects that are important for interaction between drugs and interacting proteins. In this study, interactions among 2990 FDA approved drugs and HSA were computational analyzed to unravel principles that are critical for drug‐HSA interactions. Docking results showed that drugs have higher affinity toward cavity‐1 (C1) than cavity‐2 (C2). A total of 1131 drug molecules have docking score greater than 60 while 768 molecules have docking score greater than 60 when they are docked in C2. In addition, three solvent channels have potential to direct solvent to C1 cavity while C2 does not have any effective channel. The post MD analyses demonstrated that drugs are making polar interactions with basic amino acids in the binding cavities. Verbscoside and ceftazidime both have stable low RMSD values throughout MD simulation with 2 Å on average in C1 cavity. The ligand RMSD shows less stability for verbscoside, which is around 4 Å when it is in complex with HSA in C1. The individual contribution of the residues K192, K196, R215, and R254 to ceftazidime are −1.92 ± 0.18, −3.09 ± 0.09, −2.17 ± 0.17, and − 2.32 ± 0.098, respectively. These residues contribute the binding energy of the verbscoside by −6.06 ± 0.08, −2.10 ± 0.06, and − 1.57 ± 0.03 kcal/mol individually in C1 cavity. C2 is making polar interactions with drug via R469, K472, and K488 residues and their contribution to the two drugs are −3.13 ± 0.21 kcal/mol for R469, −1.94 ± 0.18 kcal/mol for K472, and −1.96 ± 0.11 kcal/mol for K488 to total binding energy of ceftazidime. The binding energy of verbscoside is 57.17 ± 7.00 kcal/mol and Arg‐407 has the highest contribution this bind energy individually with −4.29 ± 0.12 kcal/mol. Drugs with hydrogen bond donor/acceptor chemical adducts such as verbscoside involve higher hydrogen bond formation in C1 pocket. Ceftazidime makes interaction with HSA toward hydrophobic residues, L384, L404, L487, and L488 in the C2 cavity. [ABSTRACT FROM AUTHOR]

Ruxolitinib (RUX), a Janus kinase 2 (JAK2) inhibitor, and lenalidomide (LEN), an immunomodulatory agent, have recently been proposed as a combined treatment for myelofibrosis (MF). This combination has demonstrated improved efficacy, safety, and tolerability compared to monotherapy. To further refine these findings, an efficient analytical tool is needed to simultaneously determine RUX and LEN concentrations in blood plasma. This tool would enable the study of their pharmacokinetics, drug-drug interactions, and therapeutic monitoring during MF therapy. Unfortunately, such a method has not been existed in the literature. This study presents the first HPLC method with UV detection for the simultaneous quantitation of RUX and LEN in plasma. The method was validated according to the ICH guidelines for bioanalytical method validation. It exhibited linearity in the concentration ranges of 10 to 3150 ng mL− 1 for RUX and 80 to 5200 ng mL− 1 for LEN. The limits of quantitation were determined to be 25 and 90 ng mL− 1 for RUX and LEN, respectively. All other validation parameters were satisfactory. The HPLC-UV method was successfully employed to study the pharmacokinetics and drug-drug interactions of RUX and LEN in rats following oral administration of single doses. The results demonstrated that the pharmacokinetics of both drugs were changed substantially by their coadministration. LEN exhibited synergistic effects on the maximum plasma concentration (Cmax) and total bioavailability of RUX, meanwhile it exhibited diminishing effect on the values of volume of distribution (Vd) and clearance (CL). Additionally, RUX decreased the Cmax and total bioavailability of LEN, meanwhile it increased its Vd and CL. These data suggest that the use of RUX, as a combination with LEN, is a better therapeutic approach for MF, compared with RUX as a monotherapy. The effects of LEN on the pharmacokinetics of RUX should be considered and can be useful in determining the appropriate RUX dosage and dosing regimen to achieve the desired therapeutic effect when used as a combination therapy with LEN. The method's environmental friendliness was confirmed through three comprehensive tools. This method represents a valuable tool for determining the appropriate dosage and dosing regimen of RUX in combination therapy with LEN to achieve the desired therapeutic effect. Furthermore, it can aid in predicting drug distribution in different patients and assessing the drug accumulation or insufficient drug levels in specific body compartments. [ABSTRACT FROM AUTHOR]

Purpose: Therapeutic drug monitoring (TDM) of voriconazole (VCZ) should be mandatory for all pediatric patients with invasive fungal infections (IFIs). The narrow therapeutic index, inter-individual variability in VCZ pharmacokinetics, and genetic polymorphisms cause achieving therapeutic concentration during therapy to be challenging in this population. Methods: The study included 44 children suffering from IFIs treated with VCZ. Trough concentrations (Ctrough) of VCZ ware determined by the HPLC-FLD method. Identification of the CYP2C19*2 and CYP2C19*17 genetic polymorphisms was performed by PCR–RFLP. The correlation between polymorphisms and VCZ Ctrough was analyzed. Moreover, the effect of factors such as dose, age, sex, route of administration, and drug interactions was investigated. Results: VCZ was administered orally and intravenously at a median maintenance dosage of 14.7 mg/kg/day for a median of 10 days. The VCZ Ctrough was highly variable and ranged from 0.1 to 6.8 mg/L. Only 45% of children reached the therapeutic range. There was no significant association between Ctrough and dosage, age, sex, route of administration, and concomitant medications. The frequencies of variant phenotype normal (NM), intermediate (IM), rapid (RM) and ultrarapid metabolizers (UM) were 41%, 18%, 28%, and 13%, respectively. Ctrough of VCZ were significantly higher in NM and IM groups compared with RM, and UM groups. Conclusion: The Ctrough of VCZ is characterized by inter-individual variability and a low rate of patients reaching the therapeutic range. The significant association exists in children between VCZ Ctrough and CYPC19 phenotype. The combination of repeated TDM and genotyping is necessary to ensure effective treatment. [ABSTRACT FROM AUTHOR]

Tamoxifen is an important antiestrogen for the treatment of hormone receptor‐positive breast cancer and undergoes bioactivation by CYP2D6 to its active metabolite endoxifen. Genetic variation in CYP2D6 has been linked to endoxifen levels during tamoxifen therapy. Recent studies have suggested solanidine, a glycoalkaloid phytochemical in potatoes, undergoes CYP2D6‐mediated metabolism to 4‐OH‐solanidine (m/z 414) and 3,4‐seco‐solanidine‐3,4‐dioic acid (SSDA; m/z 444). Using a retrospective cohort of 1,032 breast cancer patients on tamoxifen therapy, we examined the association of solanidine metabolites with CYP2D6 activity and its correlation with tamoxifen metabolism. Solanidine, 4‐OH‐solanidine, or SSDA was detected in 99.7% (N = 1,029) of plasma samples. Decreased solanidine metabolite ratios were found in CYP2D6 intermediate and poor metabolizers (P < 0.0001). Patients on CYP2D6 strong inhibitors had a 77.6% and 94.2% decrease in 4‐OH‐solandine/solanidine (P < 0.0001) and SSDA/solanidine (P < 0.0001), respectively. The ratio of endoxifen to tamoxifen was highly correlated with both 4‐OH‐solandine/solanidine (ρ = 0.3207, P < 0.0001) and SSDA/solanidine (ρ = 0.5022, P < 0.0001) ratios. Logistic regression modeling was used to determine that 4‐OH‐solanidine/solanidine and SSDA/solanidine ratios below 2.1 and 0.8, respectively, predicted endoxifen concentrations of <16 nM. In conclusion, solanidine, 4‐OH‐solanidine, and SSDA are diet‐derived biomarkers of CYP2D6 activity. Moreover, in patients on tamoxifen therapy, 4‐OH‐solanidine/solanidine and SSDA/solanidine predicted endoxifen levels including the inhibitory effects of concomitantly prescribed CYP2D6‐interacting medications. Accordingly, 4‐OH‐solanidine/solanidine or SSDA/solanidine ratio has the potential to be particularly useful prior to initiation of tamoxifen or for determining the impact of CYP2D6 drug interactions, as well as prior to switching from an aromatase inhibitor to tamoxifen. [ABSTRACT FROM AUTHOR]

Objective: Most patients with alcohol use disorder (AUD) regularly take medication. Alcohol interacts negatively with many commonly prescribed medications. Little is known about whether the risk of potential alcohol-medication and drug-drug interactions increases or decreases in patients with AUD during inpatient withdrawal treatment. The aim of our study was to determine the prevalence and characteristics of potential alcohol-medication and drug-drug interactions in patients with AUD before and after withdrawal treatment in an addiction unit. Design: Prospective monocentric quasi-experimental pre-post study. Methods: Medication records before and after withdrawal treatment were analyzed and screened for potential alcohol-medication (pAMI) and drug-drug interactions (pDDI) using the drugs.com classification and the AiDKlinik® electronic interaction program, respectively. Results: We enrolled 153 patients with AUD who were treated in an addiction unit of a university hospital in Germany. Of these, 67.3% experienced at least one pAMI before and 91.5% after withdrawal treatment. In total, there were 278 pAMIs classified as "mild," "moderate," or "severe" before and 370 pAMIs after withdrawal treatment. Additionally, there were 76 pDDIs classified as "moderate," "severe," or "contraindicated combinations" both before and after withdrawal treatment. Conclusion: The risk of exposure to pAMIs and pDDIs increases during inpatient withdrawal treatment in patients with AUD. Improvements in the quality of prescribing should particularly focus on the use of antihypertensives and opioids. [ABSTRACT FROM AUTHOR]

Polypharmacy (use of ≥5 concurrent medications) is highly prevalent among older adults to manage chronic diseases and is linked to adverse geriatric outcomes, including physical and cognitive functional impairments, falls, frailty, hospitalization, and mortality. Deprescribing (withdrawal) is a potential strategy to manage polypharmacy. The broad molecular changes by which polypharmacy causes harm and deprescribing may be beneficial are unknown and unfeasible to study rigorously in tissue from geriatric patients. Therefore, in a randomized controlled trial, we administered therapeutic doses of commonly used chronic medications (oxycodone, oxybutynin, citalopram, simvastatin, or metoprolol) as monotherapy or concurrently (polypharmacy) from middle‐age (12 months) to old‐age (26 months) to male C57BL/6J (B6) mice and deprescribed (gradually withdrew) treatments in a subset from age 21 months. We compared drug‐related hepatic effects by applying proteomics along with transcriptomics and histology. We found that monotherapy effects on hepatic proteomics were limited but significant changes were seen with polypharmacy (93% unique to polypharmacy). Polypharmacy altered the hepatic expression of proteins involved in immunity, and in drug, cholesterol, and amino acid metabolism, accompanied by higher serum drug levels than monotherapies. Deprescribing not only reversed some effects but also caused irreversible and novel changes in the hepatic proteome. Furthermore, our study identified several hepatic protein co‐expressed modules that are associated with clinically relevant adverse geriatric outcomes, such as mobility, frailty, and activities of daily living. This study highlights the complex molecular changes following aging, chronic polypharmacy, and deprescribing. Further exploration of these mechanistic pathways may inform management of polypharmacy and deprescribing in older adults. [ABSTRACT FROM AUTHOR]

The article delves into the significance of recognizing variations among direct-acting oral anticoagulants (DOACs) when treating patients with epilepsy, particularly in relation to concomitant antiseizure medications (ASMs). It suggests that edoxaban may be the preferred DOAC for patients with epilepsy, especially when paired with mild to moderate CYP3A-inducing ASMs. The study also cautions about potential interactions with CYP3A4/P-gp inhibiting ASMs, advising careful monitoring, especially with cannabidiol. Additionally, the article explores the association between non-vitamin K oral anticoagulants and the risk of major bleeding in patients with nonvalvular atrial fibrillation, emphasizing the importance of assessing drug interactions for effective and safe treatment. [Extracted from the article]

AbstractThe drug-drug interaction (DDI) and CYP2C19 genetic variation can lead to a high blood concentration of voriconazole. CYP2C19 is a highly genetically polymorphic enzyme, and CYP2C19*2 is more frequent among Asians associated with reduced metabolism of drugs. Clinical study found that co-administration with omeprazole significantly increased voriconazole concentrations and there was an additive effect in CYP2C19*2 allele.CYP2C19 rs4244285 (681G>A) is the key polymorphism of CYP2C19*2 allele. This study aims to describe the in vitro effects of omeprazole on CYP2C19*1 and *2 (681G>A), and determine how CYP2C19 polymorphisms influence the DDI between omeprazole and voriconazole.Using the lentiviral expression system, we successfully generated HepG2-derived cell lines stably expressing CYP2C19*1 and *2 (681G>A). The results showed that the CYP2C19 mRNA level, protein level, and enzymatic activity were lower in HepG2-CYP2C19*2 (681G>A) than HepG2-CYP2C19*1 cells. Our study also showed that the inhibition rates of omeprazole on voriconazole had no significantly differences between CYP2C19*1 and *2 (681G>A). But the IC50 of omeprazole on CYP2C19*1 slightly lower than CYP2C19*2 (681G>A).Moreover, omeprazole inhibited CYP2C19 protein level in cells carrying CYP2C19*1 and CYP2C19*2 (681G>A). Our study demonstrated that omeprazole could inhibit voriconazole metabolism in both CYP2C19*1 and CYP2C19*2 (681G>A).The drug-drug interaction (DDI) and CYP2C19 genetic variation can lead to a high blood concentration of voriconazole. CYP2C19 is a highly genetically polymorphic enzyme, and CYP2C19*2 is more frequent among Asians associated with reduced metabolism of drugs. Clinical study found that co-administration with omeprazole significantly increased voriconazole concentrations and there was an additive effect in CYP2C19*2 allele.CYP2C19 rs4244285 (681G>A) is the key polymorphism of CYP2C19*2 allele. This study aims to describe the in vitro effects of omeprazole on CYP2C19*1 and *2 (681G>A), and determine how CYP2C19 polymorphisms influence the DDI between omeprazole and voriconazole.Using the lentiviral expression system, we successfully generated HepG2-derived cell lines stably expressing CYP2C19*1 and *2 (681G>A). The results showed that the CYP2C19 mRNA level, protein level, and enzymatic activity were lower in HepG2-CYP2C19*2 (681G>A) than HepG2-CYP2C19*1 cells. Our study also showed that the inhibition rates of omeprazole on voriconazole had no significantly differences between CYP2C19*1 and *2 (681G>A). But the IC50 of omeprazole on CYP2C19*1 slightly lower than CYP2C19*2 (681G>A).Moreover, omeprazole inhibited CYP2C19 protein level in cells carrying CYP2C19*1 and CYP2C19*2 (681G>A). Our study demonstrated that omeprazole could inhibit voriconazole metabolism in both CYP2C19*1 and CYP2C19*2 (681G>A). [ABSTRACT FROM AUTHOR]

Background Hypothesis Animals Methods Results Conclusions and Clinical Importance Some studies in humans show that the concurrent use of clopidogrel and omeprazole decreases plasma clopidogrel active metabolite (CAM) concentrations and clopidogrel antiplatelet effects. Whether this drug interaction occurs in cats is unknown.We hypothesized that administration of clopidogrel with omeprazole would decrease plasma CAM concentrations and decrease clopidogrel antiplatelet effects in healthy cats.Ten domestic cats.In this 2‐sequence, 2‐period, 2‐treatment randomized crossover study, healthy cats were randomly assigned to receive clopidogrel only (18.75 mg PO q24h) or clopidogrel with omeprazole (1 mg/kg PO q12h) for 10 days, followed by a 2‐week washout period, and then the opposite treatment for another 10 days. Blood was collected by jugular venipuncture on days 0, 5, and 10. Plasma CAM concentrations were measured using high‐performance liquid chromatography‐tandem mass spectrometry. Platelet function was evaluated using Plateletworks, Multiplate Analyzer, and Platelet Function Analyzer‐100 (PFA‐100).Multiplate Analyzer and PFA‐100 detected no difference in platelet function between days or treatment groups. Plateletworks detected a significant difference (P < .001) in platelet function from day 0 to 5 and day 0 to 10 in both treatment groups but no difference between treatment groups. Plasma CAM concentrations were significantly lower on day 10 (P < .02) in cats receiving both medications versus clopidogrel only.Concurrent omeprazole and clopidogrel administration was associated with altered pharmacokinetics on day 10, but no difference in pharmacodynamics between the 2 treatment groups. The short‐term use of clopidogrel and omeprazole does not seem to alter platelet function significantly. [ABSTRACT FROM AUTHOR]

Cell membrane nanoparticles have attracted increasing interest in nanomedicine because they allow to exploit the complexity of cell membrane interactions for drug delivery. Several methods are used to obtain plasma membrane to generate cell membrane nanoparticles. Here, an optimized method combining nitrogen cavitation in isotonic buffer and sucrose gradient fractionation is presented. The method allows to obtain cell membrane fractions of high purity from both suspension and adherent cells. Comparison with other common methods for membrane extraction, where mechanical lysis using cell homogenizers is performed in isotonic or hypotonic buffers, shows that the optimized procedure yields high purity membrane in a robust and reproducible way. Procedures to mix the purified membrane with synthetic lipids to obtain cell membrane liposomes (CMLs) are presented and indications on how to optimize these steps are provided. CMLs made using crude membrane isolates or the purified membrane fractions show different uptake by cells. The CMLs made with the optimized procedure and liposomes of the same composition but without cell membrane components are thoroughly characterized and compared for their size, zeta potential, bilayer and mechanical properties to confirm membrane protein inclusion in the CMLs. Cell uptake studies confirm that the inclusion of membrane components modifies liposome interactions with cells. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion Clomipramine (CLOMI) has shown effectiveness in treating premature ejaculation but is linked to erectile dysfunction and reduced libido. Yohimbine (YOH), by contrast, is effective in treating erectile dysfunction and may improve libido. Combining CLOMI and YOH could potentially leverage the benefits of both drugs. This study aimed to investigate the interactions between these drugs and to evaluate their safety profile.A prospective, open‐labelled, single‐centre, pharmacokinetic (PK) drug–drug interaction study was performed in 15 healthy male subjects. Single‐dose and steady‐state PK were investigated using noncompartmental analysis after mono‐ and combination therapy of the 2 orally applied drugs. Plasma sampling was performed at baseline, 0.5 (YOH), 1, 1.5 (YOH), 2, 3, 4, 5, 6, 8, 12 and 24 h (CLOMI). Differences in the area under the curve after multiple dosing (MD) were determined using an equivalence boundary of 80–125%.The geometric mean ratio of the area under the curve up to 12 h for MD CLOMI (combination vs. monotherapy) was 112% (90% confidence interval: 104–120%), whereas for MD YOH this ratio was 137% (90% confidence interval: 112–168%). The study drugs were safe and well tolerated as mono‐ and combination therapy, with no major adverse events reported.A PK assessment of clomipramine and yohimbine indicated a clinically significant drug–drug interaction for MD YOH in combination with CLOMI. This might be explained by competitive, CLOMI‐related inhibition of YOH metabolism, probably mediated by cytochrome P450 2D6. However, according to European Medicines Agency guidelines, the effect can be classified as interaction absent (<1,25 fold) or minor (>1.25–<2‐fold). Given the complimentary mechanisms of action and the favourable safety profiles, the findings pave the way for future efficacy studies. [ABSTRACT FROM AUTHOR]

Glass vials are the most widely used primary containers for the packaging of parenteral products due to their optical clarity, general inertness, and hermetic properties, but under certain circumstances, they can pose safety concerns. Most of these issues are related to the potential formation of glass particulates through delamination or precipitation, resulting from the chemical interaction between the drug product and the inner surface of the glass vial. Hence, it is imperative for pharmaceutical companies to conduct product-vial compatibility studies to determine the appropriate packaging/container closure system. To support this development activity, scientists need to develop analytical methods to detect subvisible glass particulates in parenteral products, along with the appropriate positive controls, to facilitate detection and identification. This paper outlines the utilization of coaxial/episcopic and oblique illumination microscopy, combined with spectroscopic techniques, to detect thin glass particulates generated from a modified procedure. It also showcases the importance of angle-dependent lighting in visualizing positive control samples containing thin glass particulates. The analytical microscopy techniques discussed in this paper can assist scientists in selecting suitable container closure systems for developing parenteral products. [ABSTRACT FROM AUTHOR]

Letermovir (LET) is a novel antiviral agent recently approved for cytomegalovirus (CMV) prophylaxis of renal transplant patients in Japan. However, its interactions with tacrolimus (TAC), an important immunosuppressant, remain ambiguous, warranting careful evaluation considering the unique genetic and physiological characteristics of Japanese patients. Therefore, in this study, we aimed to investigate the drug-drug interactions between LET and extended-release TAC (ER-TAC) in Japanese renal transplant patients via physiologically based pharmacokinetic (PBPK) modeling. We developed PBPK models for LET and TAC, including a new model for ER-TAC, using the Simcyp simulator. We also created a virtual Japanese post-transplant population by incorporating physiological parameters specific to Japanese patients, including CYP3A5 genotypes. Our model accurately predicted the pharmacokinetics of both immediate-release and ER-TAC co-administered with LET. In the Japanese population, LET significantly increased ER-TAC exposure, with the effect varying by CYP3A5 genotype. For CYP3A5*1 carrier, the area under the curve ratio ranged from 2.33 to 2.53, while for CYP3A5*3/*3 carriers, it ranged from 2.82 to 2.86. The maximum concentration ratio was approximately 1.50 across all groups. Our findings suggest reducing the ER-TAC dose by approximately 57-60% for CYP3A5*1 carrier and 65% for CYP3A5*3/*3 carriers when co-administered with LET for Japanese renal transplant patients. Moreover, the developed model incorporating population-specific factors, such as hematocrit values and CYP3A5 genotype frequencies, is a valuable tool to evaluate complex drug interactions and guide the dosing strategies for LET and TAC in Japanese patients. Overall, this study expands the application of PBPK modeling in transplant pharmacology, contributing to the development of effective immunosuppressive strategies for Japanese renal transplant patients. [ABSTRACT FROM AUTHOR]

Providing a better understanding of what makes a compound a successful drug candidate is crucial for reducing the high attrition rates in drug discovery. Analyses of the differences between active compounds, clinical candidates and drugs require high-quality datasets. However, most datasets of drug discovery programs are not openly available. This work introduces a dataset of compound-target pairs extracted from the open-source bioactivity database ChEMBL (release 32). Compound-target pairs in the dataset either have at least one measured activity or are part of the manually curated set of known interactions in ChEMBL. Known interactions between drugs or clinical candidates and targets are specifically annotated to facilitate analyses of differences between drugs, clinical candidates, and other active compounds. In total, the dataset comprises 614,594 compound-target pairs, 5,109 (3,932) of which are known interactions between drugs (clinical candidates) and targets. The extraction is performed in an automated manner and fully reproducible. We are providing not only the datasets but also the code to rerun the analyses with other ChEMBL releases. [ABSTRACT FROM AUTHOR]

Owing to the emergence of multi‐drug resistant tuberculosis, there is a need for the exploration of new antitubercular agents. In this context, new coumarin‐based 1,2,3‐triazole hybrids were developed and evaluated for their antimicrobial activity against ESKAPE pathogens and the Mtb H37Rv strain. Among them, compounds 9 c and 12 showed MICs of 1 and 2 μg/mL, respectively, against the Mtb strain. The lead compounds exhibited a good selectivity index against Vero cells and were equally effective against ETB‐resistant and RIF‐resistant Mtb strains. Time‐kill kinetic studies revealed the bacteriostatic properties of the lead compounds, while combination studies using FDA‐approved antibiotics showed no drug interactions. Based on the structural similarity, it was envisaged that they might inhibit the DNA gyrase, which was further proved by the DNA supercoiling inhibition assay. Additionally, in silico docking studies, binding energy calculations, and ADME/T studies for the synthesized conjugates showed favourable pharmacokinetic and physicochemical characteristics. Hence, these molecules could further pave the way for discovering new potent antitubercular agents to combat AMR. [ABSTRACT FROM AUTHOR]

Asthma and cardiovascular disease (CVD) often co-exist. When a patient has both conditions, management requires an approach that addresses the unique challenges of each condition separately, while also considering their potential interactions. However, specific guidance on the management of asthma in patients with CVD and on the management of CVD in patients with asthma is still lacking. Nevertheless, health care providers need to adopt a comprehensive approach that includes both respiratory and CVD health. The management of CVD in patients with asthma requires a delicate balance between controlling respiratory symptoms and minimising potential cardiovascular (CV) risks. In the absence of specific guidelines for the management of patients with both conditions, the most prudent approach would be to follow established guidelines for each condition independently. Careful selection of asthma medications is essential to avoid exacerbation of CV symptoms. In addition, optimal management of CV risk factors is essential. However, close monitoring of these patients is important as there is evidence that some asthma medications may have adverse effects on CVD and, conversely, that some CVD medications may worsen asthma symptoms. On the other hand, there is also increasing evidence of the potential beneficial effects of asthma medications on CVD and, conversely, that some CVD medications may reduce the severity of asthma symptoms. We aim to elucidate the potential risks and benefits associated with the use of asthma medications in patients with CVD, and the potential pulmonary risks and benefits for patients with asthma who are prescribed CVD medications. [ABSTRACT FROM AUTHOR]

AbstractBotanical supplements, herbal remedies, and plant-derived products are used globally. However, botanical dietary supplements are rarely subjected to robust safety testing unless there are adverse reports in post-market surveillance. Botanicals are complex and difficult to assess using current frameworks designed for single constituent substances (e.g. small molecules or discrete chemicals), making safety assessments costly and time-consuming. The liver is a primary organ of concern for potential botanical-induced hepatotoxicity and botanical-drug interactions as it plays a crucial role in xenobiotic metabolism. The NIH-funded Drug Induced Liver Injury Network noted that the number of botanical-induced liver injuries in 2017 nearly tripled from those observed in 2004–2005. New approach methodologies (NAMs) can aid in the rapid and cost-effective assessment of botanical supplements for potential hepatotoxicity. The Hepatotoxicity Working Group within the Botanical Safety Consortium is working to develop a screening strategy that can help reliably identify potential hepatotoxic botanicals and inform mechanisms of toxicity. This manuscript outlines the Hepatotoxicity Working Group’s strategy and describes the assays selected and the rationale for the selection of botanicals used in case studies. The selected NAMs evaluated as a part of this effort are intended to be incorporated into a larger battery of assays to evaluate multiple endpoints related to botanical safety. This work will contribute to a botanical safety toolkit, providing researchers with tools to better understand hepatotoxicity associated with botanicals, prioritize and plan future testing as needed, and gain a deeper insight into the botanicals being tested. [ABSTRACT FROM AUTHOR]

The immunocompromised population was disproportionately affected by the severe acute respiratory syndrome coronavirus 2 pandemic. However, these individuals were largely excluded from clinical trials of vaccines, monoclonal antibodies, and small molecule antivirals. Although the community of scientists, clinical researchers, and funding agencies have proven that these therapeutics can be made and tested in record time, extending this progress to vulnerable and medically complex individuals from the start has been a missed opportunity. Here, we advocate that it is paramount to plan for future pandemics by investing in specific clinical trial infrastructure for the immunocompromised population to be prepared when the need arises. [ABSTRACT FROM AUTHOR]

AbstractType 2 diabetes mellitus (T2DM), responsible for most diabetes cases recorded worldwide, increases the risk of chronic wounds and amputation. Patients with T2DM appear to be more susceptible to delayed wound healing due to their treatment adherence. This review explores the specifics of polypharmacy, side effects, possible drug interactions and the importance of medication adherence for therapeutic efficacy. We discuss the effects of anti-diabetes medications on wound healing as well as the role that biofilms and microbial infections play in diabetic wounds. Inconsistent use of medications can lead to poor glycaemic control, which negatively affects the healing process of diabetic foot ulcers. Managing chronic wounds represents a substantial portion of healthcare expenditures. Biofilm-associated infections are difficult for the immune system to treat and respond inconsistently to antibiotics as these infections are slow growing and persistent. Additionally, we emphasize the critical role pharmacists play in enhancing patient adherence and optimizing diabetes treatment by offering comprehensive coverage of drugs associated with problems related to pharmacological therapy in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Drug-drug interactions (DDIs) can result in unexpected pharmacological outcomes, including adverse drug events, which are crucial for drug discovery. Graph neural networks have substantially advanced our ability to model molecular representations; however, the precise identification of key local structures and the capture of long-distance structural correlations for better DDI prediction and interpretation remain significant challenges. Results: Here, we present DrugDAGT, a dual-attention graph transformer framework with contrastive learning for predicting multiple DDI types. The dual-attention graph transformer incorporates attention mechanisms at both the bond and atomic levels, thereby enabling the integration of short and long-range dependencies within drug molecules to pinpoint key local structures essential for DDI discovery. Moreover, DrugDAGT further implements graph contrastive learning to maximize the similarity of representations across different views for better discrimination of molecular structures. Experiments in both warm-start and cold-start scenarios demonstrate that DrugDAGT outperforms state-of-the-art baseline models, achieving superior overall performance. Furthermore, visualization of the learned representations of drug pairs and the attention map provides interpretable insights instead of black-box results. Conclusions: DrugDAGT provides an effective tool for accurately predicting multiple DDI types by identifying key local chemical structures, offering valuable insights for prescribing medications, and guiding drug development. All data and code of our DrugDAGT can be found at https://github.com/codejiajia/DrugDAGT. [ABSTRACT FROM AUTHOR]

Objective: Darunavir (DRV) is a P-glycoprotein (P-gp) inhibitor. Dabigatran etexilate, prodrug of the anticoagulant dabigatran, is a P-gp probe substrate. This study evaluated the effect of single and multiple doses of DRV, coadministered with cobicistat (COBI) or ritonavir (rtv), on the pharmacokinetics (PK) of single-dose dabigatran etexilate. Methods: This was an open-label, fixed-sequence, single-center, 2-panel, phase 1 study in which healthy adult participants were equally divided over 2 panels. In panel 1, participants received single and multiple doses of DRV/COBI 800/150 mg coadministered with single-dose dabigatran etexilate 150 mg. In panel 2, participants received single and multiple doses of DRV 800 mg + rtv 100 mg coadministered with single-dose dabigatran etexilate 150 mg. Key PK parameters evaluated were maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinity (AUCinf) for free and total dabigatran. Results: Overall, 28 participants were enrolled and treated (n = 14 per panel). Dabigatran Cmax and AUCinf increased 2.64-fold after a single dose of DRV/COBI and 1.99- and 1.88-fold, respectively, after multiple doses of DRV/COBI. Dabigatran Cmax and AUCinf increased 1.64- and 1.72-fold, respectively, after a single dose of DRV + rtv and 1.22- and 1.18-fold, respectively, after multiple doses of DRV + rtv. In both panels, the most commonly reported adverse events were diarrhea and headache. Conclusion: Findings of increased dabigatran exposure with DRV/COBI or DRV + rtv coadministration indicate an inhibitory effect of single-dose boosted DRV on P-gp, and a mixed inhibitory/inductive effect of multiple doses of boosted DRV on P-gp. Trial registration: ClinicalTrials.gov, NCT04208061. Registered December 19, 2019 [ABSTRACT FROM AUTHOR]

In vitro, spheroid models have become well established in cancer research because they can better mimic certain characteristics of in vivo tumours. However, interaction with the tumour microenvironment, such as cancer-associated fibroblasts, plays a key role in tumour progression. We initially focused on the interaction of tumour cells with fibroblasts. To model this interaction, we developed a spheroid model of ovarian cancer and fibroblasts. To this end, ovarian cancer cell lines and ex vivo primary cells were simultaneously and sequentially seeded with fibroblasts in a scaffold-free system at different ratios and subsequently characterized with respect to changes in morphology, proliferation, and viability. We demonstrated that co-cultures are able to form by far more compact spheroids, especially in cells that form aggregates in mono-culture. In addition, the co-cultures were able to increase proliferation and sensitivity to cisplatin. Simultaneous seeding led fibroblasts invade the core in both cell lines and primary cells. These results show differences in formation, firmness, and size between co-culture and mono-culture. Our model is designed to better represent and characterize the mutual influencing factors of fibroblasts and tumour cells. Fibroblast-supplemented multicellular spheroids are a valuable tool for tumour microenvironment interaction and new drug discovery. [ABSTRACT FROM AUTHOR]

The document is a corrigendum for an article titled "Inhibitory effects of calcium channel blockers nisoldipine and nimodipine on ivacaftor metabolism and their underlying mechanism." The correction addresses errors in Figure 7 and Table 2 related to the unit of concentration values used. The corrected Ki values are now 3.26 and 5.87, respectively. The authors assure that these corrections do not impact the scientific conclusions of the original article. [Extracted from the article]

Background: Drug-drug interactions (DDIs) may influence the effectiveness and safety of medication treatment, which may require additional monitoring, dose adjustment or avoidance of certain drugs. DDIs involving P-glycoprotein (P-gp) affect many drugs, but current official product information is often insufficient to guide the management of these DDIs in clinical practice. The aim of this paper is to describe a protocol to assess DDIs involving P-gp and to develop and implement practice recommendations for clinically relevant P-gp-mediated DDIs that affect clinical outcomes through changes in systemic drug exposure. Methods: A combined literature review and expert opinion approach will be used according to the following seven steps: set up an expert panel (step 1), establish core concepts and definitions (step 2), select potential P-gp-modulators (i.e., P-gp-inducers and -inhibitors) and P-gp-substrates to be evaluated (step 3), select and extract evidence-based data, and present findings in standardized assessment reports (step 4), discuss and adopt classifications and practice recommendations with the expert panel (step 5), publish and integrate information and alerts in clinical decision support systems (CDSS) (step 6), (re)assessments of DDIs and potential new DDIs when new information is available or when initiated by healthcare providers (step 7). Anticipated results: The expert panel will classify potential P-gp-modulators and -substrates as clinically relevant P-gp-inducer, -inhibitor and/or -substrate and draw conclusions about which combinations of classified modulators and substrates will lead to clinically relevant DDIs. This may include the extrapolation of conclusions for DDIs where limited or no data are available, based on the pharmacological characteristics of these drugs. For (potential) DDIs that are considered to be clinically relevant, practice recommendations will be developed. Discussion: This protocol describes a standardized, evidence- and expert opinionbased assessment of P-gp-mediated DDIs that affect clinical outcomes. This approach will generate alerts with practice recommendations for clinically relevant DDIs and transparent rationales for DDIs that are considered to be irrelevant. These recommendations will improve individual patient care by supporting healthcare professionals to make consistent decisions on how to manage P-gp mediated DDIs. [ABSTRACT FROM AUTHOR]

Ivacaftor is the first potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) protein approved for use alone in the treatment of cystic fibrosis (CF). Ivacaftor is primarily metabolized by CYP3A4 and therefore may interact with drugs that are CYP3A4 substrates, resulting in changes in plasma exposure to ivacaftor. The study determined the levels of ivacaftor and its active metabolite M1 by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). We screened 79 drugs and 19 severely inhibited ivacaftor metabolism, particularly two cardiovascular drugs (nisoldipine and nimodipine). In rat liver microsomes (RLM) and human liver microsomes (HLM), the half-maximal inhibitory concentrations (IC50) of nisoldipine on ivacaftor metabolism were 6.55 μM and 9.10 μM, respectively, and the inhibitory mechanism of nisoldipine on ivacaftor metabolism was mixed inhibition; the IC50 of nimodipine on ivacaftor metabolism in RLM and HLM were 4.57 μM and 7.15 μM, respectively, and the inhibitory mechanism of nimodipine on ivacaftor was competitive inhibition. In pharmacokinetic experiments in rats, it was observed that both nisoldipine and nimodipine significantly altered the pharmacokinetic parameters of ivacaftor, such as AUC(0-t) and CLz/F. However, this difference may not be clinically relevant. In conclusion, this paper presented the results of studies investigating the interaction between these drugs and ivacaftor in vitro and in vivo. The objective is to provide a rationale for the safety of ivacaftor in combination with other drugs. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies (mAbs) are used to prevent, detect, and treat a broad spectrum of non-communicable and communicable diseases. Over the past few years, the market for mAbs has grown exponentially with an expected compound annual growth rate (CAGR) of 11.07% from 2024 (237.64 billion USD estimated at the end of 2023) to 2033 (679.03 billion USD expected by the end of 2033). Ever since the advent of hybridoma technology introduced in 1975, antibody-based therapeutics were realized using murine antibodies which further progressed into humanized and fully human antibodies, reducing the risk of immunogenicity. Some benefits of using mAbs over conventional drugs include a drastic reduction in the chances of adverse reactions, interactions between drugs, and targeting specific proteins. While antibodies are very efficient, their higher production costs impede the process of commercialization. However, their cost factor has been improved by developing biosimilar antibodies as affordable versions of therapeutic antibodies. Along with the recent advancements and innovations in antibody engineering have helped and will furtherly help to design bio-better antibodies with improved efficacy than the conventional ones. These novel mAb-based therapeutics are set to revolutionize existing drug therapies targeting a wide spectrum of diseases, thereby meeting several unmet medical needs. This review provides comprehensive insights into the current fundamental landscape of mAbs development and applications and the key factors influencing the future projections, advancement, and incorporation of such promising immunotherapeutic candidates as a confrontation approach against a wide list of diseases, with a rationalistic mentioning of any limitations facing this field. [ABSTRACT FROM AUTHOR]

Background: Drug-drug interactions (DDIs) are associated with increased or decreased adverse effects and decreased or decreased therapeutic effects. Hospitalized pediatric patients are exposed to a number of potential DDIs (pDDIs). There are limited studies on pDDIs among pediatric patients in Ethiopia. This study was aimed to evaluate the pDDIs and associated factors among hospitalized pediatric patients in Adigrat general hospital, Tigrai, northern Ethiopia. Methods: A retrospective cross-sectional study was carried out among hospitalized pediatric patients in Adigrat general hospital from 01 July 2020 to 31 August 2020. A simple random sampling technique was used to select medical charts. Micromedex 2.0 database was used to screen pDDIs. Data was analyzed using statistical package for social science version 21 and a P-value of ≤ 0.05 was considered statistically significant. Results: Of the total 146 patients studied, 100 (68.5%) were exposed for at least one pDDI. A total of 158 pDDIs consisting of 33 distinct interacting drug pairs were identified. About 19.3% of the patients had at least one major pDDI, 6.7% at least one moderate and 68.9% at least one minor pDDIs. On the other hand, 63.3% of the total pDDIs were minor and 25.9% major while 3. 8% were contraindicated pDDIs with 15.2% fair and 81.6% good level of documentation. The overall mean duration of pDDIs exposure was about 4.9 (1-23) days. The frequently occurring potential clinical consequences of pDDIs comprised increased risk of QT-interval prolongation (10.1%), theophylline toxicity (5.1%), antiepileptic toxicity (5.1%) and formation of ceftriaxone calcium precipitates (3.8%). Infant/toddler age group (adjusted odds ratio [AOR] = 31.961, 95% CI: 1.117-914.528), number of diseases (AOR = 0.255, 95% CI: 0.069-0.939) and polypharmacy (AOR = 0.276, 95% CI: 0.091-0.838) were associated with pDDIs exposures. Conclusions: A large number of pediatric patients were exposed to a various pDDIs. Age, number of diseases and polypharmacy predicted for the occurrence of pDDIs. Besides, the major severity pDDIs encounted frequently in the current study can potentially lead to a life threatening cardio-vascular toxicicty from QT-interval prolongation. Clinicians should be vigilant to pDDIs to prevent potential clinical consequences of pDDIs. Moreover, computerized drug interaction screening and clincal pharmacy services should be practiced to improve patients' safety. [ABSTRACT FROM AUTHOR]

Psychedelic therapies are an emerging class of treatments in psychiatry with great potential, however relatively little is known about their interactions with other commonly used psychiatric medications. As psychedelic therapies become more widespread and move closer to the clinic, they likely will need to be integrated into existing treatment models which may include one or more traditional pharmacological therapies, meaning an awareness of potential drug-drug interactions will become vital. This commentary outlines some of the issues surrounding the study of drug-drug interactions of this type, provides a summary of some of the relevant key results to date, and charts a way forward which relies crucially on multimodal neuroimaging investigations. Studies in humans which combine Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI), plus ancillary measures, are likely to provide the most comprehensive assessment of drug-drug interactions involving psychedelics and the relevant effects at multiple levels of the drug response (molecular, functional, and clinical). [ABSTRACT FROM AUTHOR]

Background: Drug-drug interactions (DDIs) between antiretroviral therapy (ART) and commonly used co-medications in HIV patients, especially women, impact treatment efficacy and patient safety. Objective: This study aimed to study the prevalence and types of drug-drug interactions (DDIs) between antiretroviral therapy drugs (ARTs) and comedications among a female population with HIV. Additionally, the study investigates the association of these DDIs with ART medication changes and treatment adherence. Methods: This cross-sectional study included 632 adult women living with HIV (WLHIV). Data was retrospectively extracted from patient files. Drug.com interaction checker website was used to assess DDIs between ART and non-ART medications. Changes to the ART regimen previously attributed to ART side effects or patient non-adherence were considered drug changes. Results: A total of 429 WLHIV (mean age: 44.05 ± 9.50) were eligible. The prevalence of DDIs between ART and non-ART medications was 21.4%, with 4.7% minor, 18.4% moderate, and 8.9% major interactions. The highest prevalence of DDI was among cardiovascular medication users (71.7%), followed by central nervous system drugs (69.2%). Changing medications resulted in a decrease in DDIs, with significant reductions in total and minor interactions. Participants without DDIs had better adherence to ART. DDI between ART and non-ART medications was significantly associated with ART drug change, even after accounting for side effects attributed to ARTs, indicating an independent twofold association (OR = 1.99, CI 1.04–3.77). Moreover, further adjustments for HIV viral load and CD4 + cell count did not change the significance of the association (OR = 2.01, CI 1.03–3.92). Conclusion: DDIs in WLHIV impact adherence to ART. Altering ART may not be directly related to ART side effects, but rather primarily due to interactions with non-ART medications. Modifying non-ART drug regimens can reduce the likelihood of DDIs. [ABSTRACT FROM AUTHOR]

Antibiotic‐resistant bacteria have rapidly emerged in recent years as a result of irrational use of antibiotics. The development of drug carriers that can enhance antibacterial activity of antibiotics can potentially overcome antibiotic resistance and hence has practical significance. This study addresses this need by integrating amine‐functionalized magnetic nanoparticles (AMNPs) into hydrogel microbeads composed of sodium alginate (SA) and xanthan gum (XG) for delivery of levofloxacin (LVX). Characterization of the microbeads confirmed successful AMNP–polymer interactions and demonstrated a porous structure inside the microbeads. The microbeads demonstrated pH‐sensitive drug release behavior, enabling prolonged drug release. The drug encapsulation efficiency in the hydrogel microbeads was higher after AMNP incorporation, indicating the potential roles played by the porous network and by AMNP‐LVX interactions during drug loading. The microbeads adhered to first‐order, Higuchi, and Korsmeyer‐Peppas kinetic models, suggesting that a combination of diffusion and polymer relaxation mechanisms is involved in drug release. Along with the fact that the AMNP‐incorporated microbeads exhibited enhanced antibacterial activity against various bacterial strains, our microbeads warrant further development and optimization as drug carriers for antibacterial applications. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion Dersimelagon is a novel, investigational, orally administered, selective agonist of the melanocortin‐1 receptor that has demonstrated efficacy at increasing symptom‐free light exposure and an acceptable safety profile in patients with protoporphyria. A phase 1 drug–drug interaction (DDI) study demonstrated that dersimelagon 300 mg has the potential for clinically relevant DDIs with drugs that are substrates for breast cancer resistance protein, such as atorvastatin and rosuvastatin. This study uses physiologically based pharmacokinetic (PBPK) modelling to further investigate the DDI effects at lower doses of dersimelagon with substrate drugs.The data from in silico, in vitro and in vivo studies were used to construct a PBPK model for dersimelagon to assess the DDI potential between dersimelagon and substrate drugs for cytochrome P450 3A, P‐glycoprotein, organic anion transporting polypeptide 1B1/1B3, organic anion transporter 3 and breast cancer resistance protein, including atorvastatin and rosuvastatin.The systemic exposure of atorvastatin based on the maximum plasma concentration and area under the plasma concentration–time curve was predicted to increase 1.21‐fold and 1.25‐fold, respectively, if coadministered with dersimelagon 100 mg, and 1.42‐fold and 1.45‐fold with dersimelagon 200 mg. The systemic exposure of rosuvastatin followed trends similar to atorvastatin (1.67‐fold and 1.34‐fold increase in maximum plasma concentration and area under the plasma concentration–time curve, respectively, with dersimelagon 100 mg, and 2.40‐fold and 1.69‐fold with dersimelagon 200 mg).Overall, PBPK modelling results indicate that the simulated changes in plasma exposure of atorvastatin and rosuvastatin following coadministration with dersimelagon 100 or 200 mg are not clinically significant, but caution and appropriate clinical monitoring should be recommended. [ABSTRACT FROM AUTHOR]

Objective Background Methods Results Conclusion To evaluate the pharmacodynamic (PD) and pharmacokinetic (PK) interactions between zavegepant and sumatriptan in healthy adults.Zavegepant is a high‐affinity, selective, small‐molecule calcitonin gene–related peptide receptor antagonist administered as a nasal spray approved in the United States for the acute treatment of migraine. Triptans, including sumatriptan, are a different class of drugs for acute migraine treatment and are associated with a risk of increased blood pressure (BP). Hence, it is important to study the drug–drug interactions between zavegepant and sumatriptan due to potential coadministration in clinical settings.This was a Phase 1, single‐center, partially blind, randomized, placebo‐controlled, single‐arm study. Eligible participants were males aged ≥ 18 and ≤ 40 years or females aged ≥ 18 and ≤ 50 years. On Day 1, participants received sumatriptan 2 × 6 mg subcutaneous injections (1 h apart) and were then randomized (6:1 ratio) to receive zavegepant 2 × 10 mg nasal spray (1 in each nostril) or placebo on Days 2 and 3. On Day 4, zavegepant or placebo was coadministered with sumatriptan after the second sumatriptan injection. BP, PK, and safety were evaluated at pre‐specified time points.Forty‐two participants enrolled in the study received at least one dose of any treatment and were included in the safety analyses. Forty‐one participants who completed the study were included in the BP and PK analyses. The mean (standard deviation) time‐weighted average (TWA) of mean arterial pressure (MAP [sumatriptan + zavegepant 87.2 (6.8) vs. sumatriptan 86.9 (6.0)]), diastolic BP (DBP [sumatriptan + zavegepant 72.3 (6.8) vs. sumatriptan 72.1 (6.2)]), and systolic BP (SBP [sumatriptan + zavegepant 116.8 (10.2) vs. sumatriptan 116.2 (8.6)]) did not change following zavegepant and sumatriptan coadministration on Day 4 compared to sumatriptan alone on Day 1. Statistical comparisons of the TWA of MAP, DBP, and SBP between sumatriptan and zavegepant coadministration and sumatriptan alone were similar; the differences observed were 0.04 mmHg for MAP (90% confidence interval [CI]: −0.69, 0.77 mmHg), 0.00 mmHg for DBP (90% CI: −0.76, 0.76 mmHg), and 0.33 mmHg for SBP (90% CI: −0.97, 1.63 mmHg). Sumatriptan PK after sumatriptan and zavegepant coadministration versus sumatriptan alone was similar; the comparison ratios were 102.5% (90% CI: 100.7%, 104.2%) for AUC0‐inf and 104.1% (90% CI: 98.0%, 110.6%) for Cmax. A small difference in zavegepant PK exposure after sumatriptan and zavegepant coadministration versus zavegepant alone was not considered clinically relevant: the comparison ratios were 112.4% (90% CI: 103.4%, 122.3%) for AUC0–24 and 96.7% (90% CI: 88.9%, 105.2%) for Cmax. Overall, 90% (38/42) of participants experienced ≥ 1 treatment‐emergent adverse event that was mild or moderate in severity. All treatments were generally safe and well tolerated.Coadministration of zavegepant with sumatriptan was safe and without PD or PK interactions in healthy adults. [ABSTRACT FROM AUTHOR]

Introduction: Drug Information Services (DIS) act as a source of technical and scientific information of drugs and medical devices, promoting their rational use. Objectives: To analyze and classify, according to standardized criteria, the pharmacotherapeutic queries, therapeutic groups, and drugs most frequently consulted at the DIS of the Muy Ilustre Colegio Oficial de Farmacéuticos de Valencia (MICOF). Methodology: An ambispective and cross-sectional observational study was conducted from June 1, 2021, to June 1, 2022. A total of 445 inquiries made by pharmacists from the province of Valencia were registered and analyzed, collecting the following data: drug, ATC-4 therapeutic group, and pharmacotherapeutic category of the query. Results: The most frequently consulted categories were commercialization and safety, with Proton Pump Inhibitors (PPIs, A02BC) and Vitamin K Antagonists (VKAs, B01AA) being the most consulted pharmacological groups, accounting for 2.7% and 2.3% of the total inquiries respectively. Regarding classification, 90,0% of the inquiries about acenocoumarol were about drug interactions, while 33.3% of the inquiries about PPIs were related to commercialization. Conclusions: The analysis of the inquiries received has made possible to identify the therapeutic groups, drugs and pharmacotherapeutic categories that generate the highest number of inquiries. This information is valuable for improving the efficiency of responses at the DIS, providing uniformity, and reducing errors. Additionally, it provides a comprehensive database that facilitates the standardized integration of information. [ABSTRACT FROM AUTHOR]

Limited antifungal treatment options and drug resistance require innovative approaches to effectively combat fungal infections. Combination therapy is a promising strategy that addresses these pressing issues by concurrently targeting multiple cellular sites. The drug targets usually selected for combination therapy are from different cellular pathways with the goals of increasing treatment options and reducing development of resistance. However, some circumstances can prevent the implementation of combination therapy in clinical practice. These could include the increased risk of adverse effects, drug interactions, and even the promotion of drug resistance. Furthermore, robust clinical evidence supporting the superiority of combination therapy over monotherapy is limited and underscores the need for further research. Despite these challenges, synergies detected with different antifungal classes, such as the azoles and echinocandins, suggest that treatment strategies can be optimized by better understanding the underlying mechanisms. This review provides an overview of multi-targeting combination strategies with a primary focus on Candidozyma auris infections. [ABSTRACT FROM AUTHOR]

Pedunculoside and rotundic acid, the most abundant components in plants of the genus Ilex L. (Aquifoliaceae), exhibit biological and pharmacological significance in the treatment of cardiovascular diseases. However, there have been few studies on their metabolism. This study performed a systematic metabolism study of pedunculoside and rotundic acid and evaluated their potential for herb–drug interaction. Pedunculoside or rotundic acid was incubated with human liver microsomes and recombinant human metabolic enzymes, and analyzed using LC‐Q‐TOF/MS and LC–MS/MS. Pedunculoside was found to be the most stable in human liver microsomes, whereas rotundic acid was easily metabolized. Eight pedunculoside metabolites and six rotundic acid metabolites were detected and tentatively identified through hydroxylation, glucuronidation, acetylation, and glucose conjugation. Hydroxylation of pedunculoside is mainly catalyzed by CYP3A4/5 and partly by CYP2C8. Hydroxylation of rotundic acid is almost exclusively catalyzed by CYP3A4/5, and its glucuronidation reaction is mediated by UGT1A4. Neither pedunculoside nor rotundic acid showed CYP inhibition (IC50 values > 50 μM) with the probe substrates of major CYP isoforms during incubation with human liver microsomes. This study is the first investigation into the in vitro metabolism of pedunculoside and rotundic acid using human liver microsomes. It also aims to assess their potential as perpetrators of drug–drug interactions involving CYP enzymes. The comprehensive metabolism and drug interaction studies of pedunculoside and rotundic acid enable us to evaluate and manage potential risks with their use in pharmacotherapy. [ABSTRACT FROM AUTHOR]

Objective: This study was undertaken to assess the effectiveness/tolerability of adjunctive cenobamate, variations in the load of concomitant antiseizure medications (ASMs) and predictors of clinical response in people with focal epilepsy. Methods: This was a retrospective study at 21 centers participating in the Italian Expanded Access Program. Effectiveness outcomes included retention and responder rates (≥50% and 100% reduction in baseline seizure frequency). Tolerability/safety outcomes included the rate of treatment discontinuation due to adverse events (AEs) and their incidence. Total drug load was quantified as the number of concomitant ASMs and total defined daily dose (DDD). Concomitant ASMs were also classified according to their mechanism of action and pharmacokinetic interactions to perform explorative subgroup analyses. Results: A total of 236 subjects with a median age of 38 (Q1–Q3 = 27–49) years were included. At 12 months, cenobamate retention rate was 78.8% and responders were 57.5%. The seizure freedom rates during the preceding 3 months were 9.8%, 12.2%, 16.3%, and 14.0% at 3, 6, 9, and 12 months. A higher percentage of responders was observed among subjects treated with clobazam, although the difference was not statistically significant. A total of 223 AEs were recorded in 133 of 236 participants, leading to cenobamate discontinuation in 8.5% cases. At 12 months, a reduction of one or two concomitant ASMs occurred in 42.6% and 4.3% of the subjects. The median total DDD of all concomitant ASMs decreased from 3.34 (Q1–Q3 = 2.50–4.47) at baseline to 2.50 (Q1–Q3 = 1.67–3.50) at 12 months (p <.001, median percentage reduction = 22.2%). The highest rates of cotreatment withdrawal and reductions in the DDD were observed for sodium channel blockers and γ‐aminobutyric acidergic modulators (above all for those linked to pharmacokinetic interactions), and perampanel. Significance: Adjunctive cenobamate was associated with a reduction in seizure frequency and in the burden of concomitant ASMs in adults with difficult‐to‐treat focal epilepsy. The type of ASM associated did not influence effectiveness except for a favorable trend with clobazam. [ABSTRACT FROM AUTHOR]

The interest in transporter‐mediated drug interactions has been increasing in the field of drug development. In this study, we measured the plasma and urinary concentrations of coproporphyrin (CP) I and CP III as endogenous substrates for organic anion‐transporting polypeptide (OATP) using chimeric mice with human hepatocytes (PXB mice) and examined the influence of an OATP inhibitor, rifampicin (RIF). CP I and CP III were actively taken up intracellularly, and RIF inhibited the uptake in a concentration‐dependent manner for both CP I and CP III in human hepatocytes (PXB‐cells). Single doses of RIF at 10 and 30 mg/kg were orally or intravenously administered to PXB mice and wild‐type ICR mice. Plasma concentrations (AUC0‐8h) of CP I increased in both mice. However, a marked increase in CP III was only observed in ICR mice, after intravenous administration of RIF at 30 mg/kg. The IC50 values of RIF for intracellular CP I/III uptake and the unbound plasma concentrations of RIF suggested that the increase in plasma CP I is associated with the exposure of RIF to OATPs. The 24‐h cumulative urinary excretions of CP I and CP III increased in both mice, but more markedly in PXB mice. Thus, RIF increased the plasma and urinary concentrations of CP I and CP III in the mice, as reported in humans, and CP I may be a more sensitive biomarker of OATP‐mediated drug interactions in PXB mice. [ABSTRACT FROM AUTHOR]

Background Drug–drug interactions between antiretroviral treatment (ART) and cytostatics may have a negative impact in the prognosis of people with HIV (PWH) and cancer. Objective The objective of this study is to evaluate the impact of the implementation of interdisciplinary management and the type of ART in PWH diagnosed with lymphoid neoplasms. Methods This is a multicentric, retrospective observational cohort study including PWH diagnosed with lymphoid neoplasm who started first-line chemotherapy between 2008 and 2020. Demographic, clinical and therapeutic variables were obtained from the electronic medical records and associated with 5-year progression-free survival (PFS) and overall survival (OS) using Cox proportional hazard models. Results A total of 118 individuals were included. Boosted ART was being used in 55 (46.6%) cases at the time of neoplasm diagnosis. The Infectious Diseases or the Pharmacy Department was consulted before starting chemotherapy in 79/118 (66.9%) cases. Interdisciplinary management resulted in fewer subjects taking boosted ART (17.7% versus 71.8%, P  < 0.001) and more subjects using unboosted integrase strand transfer inhibitor–based ART (74.7% versus 7.7%, P  < 0.001). The use of boosted ART with chemotherapy was associated with worse 5-year PFS (P  = 0.003) and 5-year OS (P  = 0.016). There was a trend towards better 5-year PFS and OS when interdisciplinary management was implemented, with significant differences for individuals receiving boosted ART at neoplasm diagnosis (P  = 0.0246 and P  = 0.0329, respectively). Conclusions Our findings underscore the significant impact of the type of ART on the prognosis of PWH undergoing chemotherapy. Encouraging collaborative management between oncologists, pharmacists and HIV teams for these patients enhances PFS and OS rates. [ABSTRACT FROM AUTHOR]

6-thioguanine (6-TG) is an antimetabolite drug of purine structure, approved by the FDA for the treatment of acute myeloid lesukemia, and it is of interest in treating other diseases. The interaction of drugs with matrices is of interest to achieving a delayed, sustained, and local release. The interaction of 6-TG with an aluminum metal–organic framework (Al-MOF) DUT-4 is studied using a novel experimental approach, namely, mechano-chemistry by liquid-assisted grinding (LAG). The bonding of 6-TG to the DUT-4 matrix in the composite (6-TG)(DUT-4) was studied using ATR-FTIR spectroscopy and XRD. This interaction involves amino groups and C and N atoms of the heterocyclic ring of 6-TG, as well as the carboxylate COO− and (Al)O-H groups of the matrix, indicating the formation of the complex. Next, an in vitro delayed release of 6-TG was studied from composite powder versus pure 6-TG in phosphate buffered saline (PBS) at 37 °C. Herein, an automated drug dissolution apparatus with an autosampler was utilized, and the molar concentration of the released 6-TG was determined using an HPLC–UV analysis. Pure 6-TG shows a quick (<300 min) dissolution, while the composite gives the dissolution of non-bonded 6-TG, followed by a significantly (factor 6) slower release of the bonded drug. Each step of the release follows the kinetic pseudo-first-order rate law with distinct rate constants. Then, a pharmaceutical shaped body was prepared from the composite, and it yields a significantly delayed release of 6-TG for up to 10 days; a sustained release is observed with the 6-TG concentration being within the therapeutically relevant window. Finally, the composite shows a time-dependent (up to 9 days) stronger inhibition of leukemia MV-4-11 cell colonies than 6-TG. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer is most commonly diagnosed in males after the age of 55 years. These patients are also at risk for cardiovascular disease and venous thromboembolism requiring antithrombotic therapy. Prostate cancer treatments, such as androgen receptor axis-targeted therapies (ARATs, i.e., abiraterone acetate, apalutamide, darolutamide, and enzalutamide), may interact with common antithrombotic medications like warfarin, clopidogrel, and the direct oral anticoagulants. However, the data detailing the clinical outcomes of patients treated with these combinations are limited. We undertook a comprehensive review of the literature and modified Delphi process to enable development of an evidence-based consensus document for the co-prescribing of ARATs with antithrombotic medications. Our assessments relied heavily on pharmacokinetic data and extrapolation from drug interaction studies of similarly metabolized drugs, highlighting the need for more research into the clinical impact of drug interactions in prostate cancer patients. Nonetheless, we provide a practical framework to support clinicians in day-to-day therapeutic decision making. Background/Objectives: Abiraterone acetate, apalutamide, darolutamide, and enzalutamide, which make up the androgen receptor axis-targeted therapies (ARATs) drug class, are commonly used in the management of prostate cancer. Many patients on ARATs also receive oral antithrombotic therapy (i.e., anticoagulants or antiplatelets). The concomitant use of ARATs and antithrombotic therapies creates the potential for clinically relevant drug–drug interactions, but the literature regarding the actual consequences of these interactions, and guidance for co-prescribing, is limited. We assembled a multidisciplinary panel of experts and provided them with clinical information derived from a comprehensive literature review regarding the drug–drug interactions between ARATs and antithrombotic therapies. Methods: A three-stage modified electronic Delphi process was used to gather and consolidate opinions from the panel. Each stage consisted of up to three rounds of voting to achieve consensus on which ARAT/antithrombotic therapy drug pairs warrant attention, the possible clinical consequences of drug–drug interactions, and suggested actions for management. Results: The panel achieved consensus to avoid 11 ARAT/antithrombotic therapy drug pairs and modify therapy for eight pairs. Assessments relied heavily on pharmacokinetic data and extrapolation from drug–drug interaction studies of similarly metabolized drugs. Conclusions: This e-Delphi process highlights the need for further research into the clinical impact of ARAT/antithrombotic drug interactions. Nonetheless, the suggested actions aim to provide clinicians with a practical framework for therapeutic decision making. [ABSTRACT FROM AUTHOR]