Search

It is estimated that approximately 66% of Kazakhstan's territory is susceptible to desertification. One of the most significantly affected regions in terms of land degradation is the Ile-Balkhash Basin, where environmental pressures have intensified due to factors such as water scarcity, soil erosion and unsustainable land use practices. This study aims to evaluate the dynamics and risk rates of desertification, as well as its severity, in the Ile-Balkhash region. To achieve the set goal of objectives, a variety of methods were employed, including desertification divided index (DDI) for the identification of desertification dynamics, correlation analysis for the detection of relationships between different indicators, and Principal Component Analysis (PCA) for the modelling of the desertification risk rate in the study area. The spatial distribution of desertification degrees (severe, high, medium, low, and non-desertification) was identified using DDI methodologies. The results indicate that the area of severe desertification in the dry region exhibited a decline by 2020, followed by an increase. The area of high desertification and non-desertification regions has increased, while medium and low desertification areas remained relatively unchanged. The northern part of the region is experiencing the most rapid increase in DDI due to human agricultural activities and landscape features. The results of the correlation analysis indicate that precipitation is the primary factor influencing the spatial distribution of desertification. In addition, the results of the PCA model based on spectral indices indicate that the northern part of the region, where land use for pasture is prevalent, is the most vulnerable to desertification. The potential for further land degradation is heightened by the current mismanagement of land and the failure to adequately address shifting climate conditions. Factors such as temperature fluctuations, overgrazing, and specific landscape features serve to exacerbate the process of desertification. This comprehensive examination of land desertification can facilitate the formulation of effective policy strategies for the implementation of land rehabilitation plans in the Ile-Balkhash region and arid areas of southern Kazakhstan. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 infection represents a new challenge for solid organ transplantation (SOT) with evolving recommendations. A cross-sectional survey was performed (February–June 2024) to describe practices among Member States of the Council of Europe (COE) on the use of organs from deceased donors with resolved or active SARS-CoV-2 infection. Overall, 32 out of 47 Member States with a transplant program participated in the study. Four (12.5%) countries did not use organs from deceased donors either with resolved or with active SARS-CoV-2 infection and 8 (25%) countries accepted organs only from deceased donors with resolved SARS-CoV-2 infection. Donor evaluation for SARS-CoV-2 included universal screening with standard PCR testing on respiratory specimens generally (61.4%) performed within 24 h prior to organ recovery. Further microbiological, immunological and radiological investigations varied. Most waitlisted patients receiving organs from a deceased donor with active (94.5%) or resolved (61.5%) SARS-CoV-2 infection were preferred to have natural, vaccine-induced or hybrid SARS-CoV-2 immunity. Most countries did not require recipients to undergo specific anti-SARS-CoV-2 treatment as pre-exposure (0%), post-exposure prophylaxis (15.4%) or modification of immunosuppression regimen (24%). This study highlights similarities and heterogeneities in the management of SARS-CoV-2 positive donors between COE countries, and a potential to safely expand donors' pool. [ABSTRACT FROM AUTHOR]

A novel dual PI3K α/δ inhibitor, TQ‐B3525, has been developed for the targeted treatment of lymphoma and solid tumors. TQ‐B3525 is primarily metabolized by CYP3A4 and FOM3, while also serving as a substrate for the P‐glycoprotein transporter. The aim of this study was to anticipate the drug–drug interaction (DDI) of TQ‐B3525 and its two metabolites with CYP3A4 enzyme potent inducer (rifampicin) and CYP3A4/P‐gp inhibitor (itraconazole) utilizing a physiologically based pharmacokinetic (PBPK) modeling approach. Clinical data from healthy and cancer patient adults were employed to construct and evaluate the PBPK model for TQ‐B3525, M3, and M8‐3. Models involving rifampicin combined with midazolam, itraconazole combined with midazolam or digoxin were utilized to showcase the robustness of evaluating DDI effects. The simulated drug exposure of TQ‐B3525, M3, and M8‐3 in healthy and patient adults were consistent with clinical data, and the mean fold error values were within the acceptable ranges. The simulated results of positive substrates correspond to those reported in the literature. Co‐administration with rifampicin reduces Cmax and AUC of TQ‐B3525 to 76.1% and 46.0%, while increasing the levels of M3 and M8‐3. With itraconazole, Cmax and AUC of TQ‐B3525 rise to 131% and 204%, but decrease substantially for M3 and M8‐3. PBPK model simulation results showed that the systemic exposure of TQ‐B3525 was significantly affected when co‐administered with CYP3A4/P‐gp inducers and inhibitors. This indicates that the combination with strong inducers and inhibitors should be carefully avoided or adjust the dosage of TQ‐B3525 in clinic. [ABSTRACT FROM AUTHOR]

3,4-Methylenedioxymethamphetamine (MDMA) is being investigated in controlled clinical trials for use as an adjunct medication treatment for post-traumatic stress disorder. MDMA is metabolized by N-demethylation, primarily by CYP2D6, to its main inactive metabolite, 4-hydroxy-3-methoxymethamphetamine. It is also metabolized to a lesser extent by CYP1A2, CYP2B6, and CYP3A4 to its active metabolite, 3,4-methylenedioxyamphetamine. Considering the extensive hepatic metabolism and excretion, MDMA use in psychiatry raises concerns over drug-induced liver injury (DILI), a rare but dangerous event. Majority of the drugs withdrawn from the market for liver injury caused death or transplantation at frequencies under 0.01%. Unfortunately, markers for liver injury were not measured in most published clinical trials. At the same time, no visible DILI-related symptoms and adverse events were observed. Idiosyncratic DILI cases are rarely registered during clinical trials due to their rare nature. In this study, we surveyed a larger, over 1,500, and a more diverse set of reports from the FDA Adverse Event Reporting System and found 23 cases of hepatic injury and hepatic failure, in which MDMA was reported to be taken in addition to one or more substances. Interestingly, 22 out of 23 cases had one or more listed drugs with a known DILI concern based on the FDA's DILIrank dataset. Furthermore, only one report had MDMA listed as the primary suspect. Considering the nearly 20 million doses of MDMA used annually, this single report is insufficient for establishing a significant association with DILI.

Unexpected donor‐derived fungal infections represent a rare but potentially fatal complication in lung transplant (Tx) recipients. Timely communication of the results of donor cultures and prompt treatment of recipients are crucial to mitigate the consequences of donor‐derived transmissions. In this prospective cohort study, all consecutive patients who underwent lung transplantation from 2015 to 2022 were included. In December 2015, a Local Active Surveillance System has been implemented to provide biovigilance of donor culture results and optimize recipients' management. The aim of this study is to investigate the incidence of unexpected, mold‐positive cultures among lung donors and the rate of transmission to recipients. Furthermore, management strategies and outcome of recipients with mold transmission are described. In case of isolation of the same mold in donor and recipient cultures, when possible, transmission was confirmed by dendrogram analysis. During the study period, 82 lung Tx were performed from 80 donors. The prevalence of donors with "unexpected" mold isolation from the respiratory tract was 3.75% (3/80). Isolated molds were Aspergillus niger, Rhizopus oryzae, and Aspergillus flavus. Transmissions occurred in all the three cases (100%) with a mean time of 5 days from lung Tx but none of the recipients developed invasive mold disease. Our Local Active Surveillance System allowed prompt recognition of lung donors unexpected mold colonization. Even though transmission occurred, introduction of early targeted antifungal therapy prevented potential catastrophic consequence of mold donor‐derived infection in the immediate post‐Tx period. [ABSTRACT FROM AUTHOR]

Objective: This study assessed the pharmacokinetic (PK) interactions between clarithromycin (a P-glycoprotein [P-gp] inhibitor) and four direct oral anticoagulants (DOACs) (P-gp substrates) using physiologically based PK (PBPK) models to elucidate the influence of P-gp in the interaction between them. Methods: PBPK models for clarithromycin, DABE–dabigatran (DAB), rivaroxaban, apixaban, and edoxaban were constructed using GastroPlus™ (version 9.9), based on physicochemical data and PK parameters from the literature. The models were optimized and validated in healthy subjects. We evaluated the predictive performance of the established model and further assessed the impact of P-gp on the PK of the four DOACs. Successfully validated models were then used to evaluate potential drug–drug interactions (DDIs) between clarithromycin and the DOACs. Results: The established PBPK models accurately described the PK of clarithromycin, DABE–DAB, rivaroxaban, apixaban, and edoxaban. The predicted PK parameters (Cmax, Tmax, AUC0-t) were within 0.5–2 times the observed values. A sensitivity analysis of P-gp parameters indicated that an increase in P-gp expression was reduced by in vivo exposure to DOACs. The models demonstrated good predictive ability for DDIs between clarithromycin and the anticoagulants, and the ratio of the predicted values to the observed values of Cmax and the area under the curve (AUC) in the DDI state was within the range of 0.5–2. Conclusions: Comprehensive PBPK models for clarithromycin, DABE–DAB, rivaroxaban, apixaban, and edoxaban were developed, which can effectively predict DDIs mediated by P-gp's function. These models provide theoretical support for clinical dose adjustments and serve as a foundation for future PBPK model development for DOACs under specific pathological conditions. [ABSTRACT FROM AUTHOR]

The simultaneous use of two or more drugs in clinical treatment may raise the risk of a drug–drug interaction (DDI). DDI prediction is very important to avoid adverse drug events in combination therapy. Recently, deep learning methods have been applied successfully to DDI prediction and improved prediction performance. However, there are still some problems with the present models, such as low accuracy due to information loss during molecular representation or incomplete drug feature mining during the training process. Aiming at these problems, this study proposes an accurate and simple framework named PTB-DDI for drug–drug interaction prediction. The PTB-DDI framework consists of four key modules: (1) ChemBerta tokenizer for molecular representation, (2) Bidirectional Long Short-Term Memory (BiLSTM) to capture the bidirectional context-aware features of drugs, (3) Multilayer Perceptron (MLP) for mining the nonlinear relationship of drug features, and (4) interaction predictor to perform an affine transformation and final prediction. In addition, we investigate the effect of dual-mode on parameter-sharing and parameter-independent within the PTB-DDI framework. Furthermore, we conducted comprehensive experiments on the two real-world datasets (i.e., BIOSNAP and DrugBank) to evaluate PTB-DDI framework performance. The results show that our proposed framework has significant improvements over the baselines based on both datasets. Based on the BIOSNAP dataset, the AUC-ROC, PR-AUC, and F1 scores are 0.997, 0.995, and 0.984, respectively. These metrics are 0.896, 0.873, and 0.826 based on the DrugBank dataset. Then, we conduct the case studies on the three newly approved drugs by the Food and Drug Administration (FDA) in 2024 using the PTB-DDI framework in dual modes. The obtained results indicate that our proposed framework has advantages for predicting drug–drug interactions and that the dual modes of the framework complement each other. Furthermore, a free website is developed to enhance accessibility and user experience. [ABSTRACT FROM AUTHOR]

As the DDI community continues to grow, an increasing number of repositories are providing their metadata in various DDI formats. However, the current landscape of DDI metadata standards usage is not well understood. Understanding this landscape is crucial as it helps identifying usage patterns, improve interoperability, and guide future developments. To address this research gap, we investigated the availability and comprehensive element usage of DDI standards across 29 repositories registered on the platform re3data.org, using the OAI-PMH API. By analyzing approximately, a quarter of a million metadata records in DDI-Codebook format, we summarized statistics on the usage of popular DDI elements and their distribution across repositories. Our findings may have implications for the deployment of DDI metadata and the further development of these standards. They also inform researchers and data stewards about how DDI-Codebook is utilized by the community. Overall, this investigation underscores the value of openly available metadata in supporting research and achieving the goals of the FAIR data movement. [ABSTRACT FROM AUTHOR]

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]

The co‐administration of dapagliflozin (DPF) and sacubitril/valsartan (LCZ696) has emerged as a promising therapeutic approach for managing heart failure. Given that DPF and LCZ696 are substrates for P‐glycoprotein, there is a plausible potential for drug–drug interactions when administered concomitantly. To investigate the pharmacokinetic changes when these drugs are co‐administered, we have established and validated a liquid chromatography–tandem mass spectrometry (LC–MS/MS) method capable of simultaneously detecting DPF, LBQ657 (the active metabolite of sacubitril) and valsartan in rat plasma. This method has demonstrated selectivity, sensitivity, and accuracy. Drug–drug interactions were examined by the LC–MS/MS method. The mechanisms were investigated using everted intestinal sac models and Caco‐2 cells. The results showed that DPF significantly increased the area under the curve (AUC(0–t)) (3,563.3 ± 651.7 vs. 7,146.5 ± 1,714.9 h μg/L) of LBQ657 (the active metabolite of sacubitril) and the AUC(0–t) (24,022.4 ± 6,774.3 vs. 55,728.3 ± 32,446.3 h μg/L) of valsartan after oral co‐administration. Dapagliflozin significantly increased the amount of LBQ657 and valsartan in intestinal sacs by 1‐ and 1.25‐fold at 2.25 h. Caco‐2 cell uptake studies confirmed that P‐glycoprotein is the transporter involved in this interaction. This finding enhances the understanding of drug–drug interactions in the treatment of heart failure and provides a guidence for clinical therapy. [ABSTRACT FROM AUTHOR]

It is estimated that approximately 66% of Kazakhstan’s territory is susceptible to desertification. One of the most significantly affected regions in terms of land degradation is the Ile-Balkhash Basin, where environmental pressures have intensified due to factors such as water scarcity, soil erosion and unsustainable land use practices. This study aims to evaluate the dynamics and risk rates of desertification, as well as its severity, in the Ile-Balkhash region. To achieve the set goal of objectives, a variety of methods were employed, including desertification divided index (DDI) for the identification of desertification dynamics, correlation analysis for the detection of relationships between different indicators, and Principal Component Analysis (PCA) for the modelling of the desertification risk rate in the study area. The spatial distribution of desertification degrees (severe, high, medium, low, and non-desertification) was identified using DDI methodologies. The results indicate that the area of severe desertification in the dry region exhibited a decline by 2020, followed by an increase. The area of high desertification and non-desertification regions has increased, while medium and low desertification areas remained relatively unchanged. The northern part of the region is experiencing the most rapid increase in DDI due to human agricultural activities and landscape features. The results of the correlation analysis indicate that precipitation is the primary factor influencing the spatial distribution of desertification. In addition, the results of the PCA model based on spectral indices indicate that the northern part of the region, where land use for pasture is prevalent, is the most vulnerable to desertification. The potential for further land degradation is heightened by the current mismanagement of land and the failure to adequately address shifting climate conditions. Factors such as temperature fluctuations, overgrazing, and specific landscape features serve to exacerbate the process of desertification. This comprehensive examination of land desertification can facilitate the formulation of effective policy strategies for the implementation of land rehabilitation plans in the Ile-Balkhash region and arid areas of southern Kazakhstan.

This study aimed to investigate the impact of the drug–drug interaction between rivaroxaban and amiodarone on the clinical outcomes in patients with non-valvular atrial fibrillation (NVAF), focusing on pharmacokinetic and pharmacodynamic (PK/PD) aspects. A prospective study enrolling 174 patients with NVAF who were treated with rivaroxaban was conducted. The patients were divided into two groups based on postoperative antiarrhythmic and anticoagulation strategies: the rivaroxaban group (Control group) and the rivaroxaban plus amiodarone group (Riv/Amio group). The trough plasma concentrations (Ctrough) of rivaroxaban, activated partial thromboplastin time (APTT), prothrombin time (PT), and the clinical outcomes between the two groups were compared. Patients receiving 20 mg of rivaroxaban in the Riv/Amio group had a higher concentration of rivaroxaban Ctrough than those in the Control group (p = 0.009). Furthermore, in patients with moderate to severe renal impairment, rivaroxaban Ctrough was significantly increased in the Riv/Amio group. There was no significant difference in PT and APTT between the two groups. Regarding the clinical outcomes, the combination of rivaroxaban and amiodarone medication was associated with a higher incidence of bleeding events (p = 0.041; HR = 2.83, 95% CI 1.05–7.66) and clinically relevant non-major bleeding (p = 0.021; HR = 3.65, 95% CI 1.21–10.94). Finally, independent risk factors for bleeding in NAVF patients treated with rivaroxaban were identified as its combination with amiodarone (p = 0.044; OR = 2.871, 95% CI 1.028–8.023). The combination of rivaroxaban and amiodarone led to changes in rivaroxaban pharmacokinetics and an elevated risk of bleeding events. Therefore, physicians prescribing rivaroxaban medications should assess the potential bleeding risk associated with the concurrent use of amiodarone, particularly in patients with renal impairment. [ABSTRACT FROM AUTHOR]

1. Antibody-drug conjugates (ADCs) have demonstrated impressive clinical usefulness in treating several types of cancer, with the notion of widening of the therapeutic index of the cytotoxic payload through the minimisation of the systemic toxicity. Therefore, choosing the most appropriate payload molecule is a particularly important part of the early design phase of ADC development, especially given the highly competitive environment ADCs find themselves in today.2. The focus of the current review is to describe critical attributes/considerations needed in the discovery and ultimately development of cytotoxic payloads in support of ADC design. In addition to potency, several key dispositional characteristics including solubility, permeability and bystander effect, pharmacokinetics, metabolism, and drug-drug interactions, are described as being an integral part of the integrated activities required in the design of clinically safe and useful ADC therapeutic agents. [ABSTRACT FROM AUTHOR]

Arid coastal regions are threatened by land desertification, which poses a serious threat to desert ecosystems, urban areas, and sustainability on a local as well as global scale. The present study aims to map desertification and the degree of its severity over the Jazan province on the western coast of Saudi Arabia. This investigation was conducted through the integration of remote sensing data (2001 and 2020) and statistical techniques. A scatter diagram, Karl Pearson correlation coefficient, and significance p-value test were performed on various spectral indices and tasseled cap transformation (TCT) derivative matrices to determine the strong significant relation of the spectral indices combination. Based on these analyses, the desertification degree index (DDI) was developed using a NDVI–TCG combination. The desertification grades were mapped and categorized into five classes, namely, non-desertification, low, moderate, severe, and extreme desertification. The results indicated that the spatial distribution of desertification grades declined from west to east during the period from 2001 to 2020. The degree of desertification improved during the study period since there was a significant reduction in extremely serious desertification land by 15.5% and an increase in weak desertification land by 7.8%. The dynamic changes in the DDI classes in the Jazan province mainly involve transformation from extremely serious to serious, serious to moderate, and moderate to weak, with areas of 2268.1 km2, 1518.5 km2, and 1062.5 km2, respectively. Generally, over the 19-year period, the restoration of vegetated areas accounted for 41.99% of the total study area, while desertification degradation land represented 15.57% of the total area of the Jazan province. [ABSTRACT FROM AUTHOR]

Evidence supporting the effectiveness of Antimicrobial Stewardship (AMS) Programs in the emergency department (ED) setting is limited. We conducted a prospective cohort study to assess the efficacy of an AMS program in an ED and a short-stay observation unit. The intervention included periodic prospective audits (twice a week), conducted by four infectious disease consultants. Primary outcomes included the difference in the hospital mortality rate, antibiotic consumption, and the incidence of bloodstream infections (BSI) caused by multidrug resistant (MDR) bacteria, before March 2020–February 2021 and after March 2021–February 2022 when the program was implemented. Interrupted time-series analysis was performed to assess the effect of our program. During the 12-month program, we performed 152 audits and evaluated 366 antibiotic therapies out of a total of 853 patients admitted. In the intervention period, we observed a non-statistically significant decrease in total antibiotic consumption, with a change in level of − 31.2 defined daily dose/100 patient-days (PD) (p = 0.71). Likewise, we found no significant variations in the rate of BSI due to MDR Gram-positive (CT − 0.02 events/PD, p = 0.84), MDR Gram-negative bacteria (CT 0.08, p = 0.71), or Candida spp. (CT 0.008, p = 0.86). Conversely, we found a significant decrease in the mortality rate between the pre- and post-intervention periods (− 1.98 deaths/100 PD, CI − 3.9 to − 0.007, p = 0.049). The Antibiotic Stewardship Program in the ED was associated with a significant decrease in the mortality rate. More high-quality studies are needed to determine the most effective ASP strategies in this unique setting. [ABSTRACT FROM AUTHOR]

In the early stages of drug discovery, adequate evaluation of the potential drug–drug interactions (DDIs) of drug candidates is important. Several CYP3A activators are known to lead to underestimation of DDIs. These compounds affect midazolam 1'-hydroxylation but not midazolam 4-hydroxylation. We used both metabolic reactions of midazolam to evaluate the activation and inhibition of CYP3A activators simultaneously. For our CYP inhibition assay using cocktail probe substrates, simultaneous liquid chromatography-tandem mass spectrometry monitoring of 1'-hydroxymidazolam and 4-hydroxymidazolam for CYP3A was established in addition to monitoring of 4-hydroxydiclofenac and 1'-hydroxybufuralol for CYP2C9 and CYP2D6. The results of our cocktail inhibition assay were well correlated with those of a single inhibition assay, as were the estimated inhibition parameters for typical CYP3A inhibitors. In our assay, a proprietary compound that activated midazolam 1'-hydroxylation and tended to inhibit 4-hydroxylation was evaluated along with known CYP3A activators. All compounds were well characterised by comparison of the results of midazolam 1'- and 4-hydroxylation. In conclusion, our CYP cocktail inhibition assay can detect CYP3A activation and assess the direct and time-dependent inhibition potentials for CYP3A, CYP2C9, and CYP2D6. This method is expected to be very efficient in the early stages of drug discovery. [ABSTRACT FROM AUTHOR]

Enarodustat is an orally available hypoxia‐inducible factor‐prolyl hydroxylase inhibitor which can correct the erythropoietic capacity and improve anemia in chronic kidney disease. Sevelamer carbonate, a non‐calcium‐based polymeric resin, is one of the commonly prescribed agents for the management of hyperphosphatemia in patients undergoing hemodialysis. This was an open‐label, crossover study in healthy male subjects (N = 12) that evaluated the effect of sevelamer carbonate (2400 mg) on the bioavailability of enarodustat (25 mg) when the 2 drugs were administered together (Treatment B) or when enarodustat was administered 3 hours after (Treatment C) or 1 hour before (Treatment D) sevelamer carbonate compared to enarodustat alone (Treatment A). With coadministration of the 2 drugs (Treatment B), enarodustat Cmax and AUCinf reductions were 53% and 45%, respectively. For Treatment C, Cmax and AUCinf reductions were 11% and 6%, respectively, and for Treatment D the corresponding values were 8% and 20%. Thus, coadministration of enarodustat and sevelamer carbonate resulted in a substantial reduction (≈50%) in the oral bioavailability of enarodustat. However, the interaction was substantially mitigated by staggering the administration of enarodustat and sevelamer carbonate. Administration of 4 single oral doses of enarodustat 25 mg, with or without sevelamer carbonate, were safe and well tolerated in this study. [ABSTRACT FROM AUTHOR]

Mavacamten is a potential inducer of cytochrome P450 (CYP) 3A4 and, as such, could reduce the exposure of the active components of oral contraceptives, ethinyl estradiol (EE) and norethindrone (NOR), where CYP3A4 is involved in metabolism. This study assessed if repeat doses of mavacamten led to a drug–drug interaction with EE and/or NOR. This was an open‐label study in healthy women. In Period 1, participants received 35 mcg of EE and 1 mg of NOR. In Period 2, participants received oral loading doses of mavacamten 25 mg on Days 1–2, 15 mg/day on Days 3‒17, and 35 mcg of EE and 1 mg of NOR on Day 15. Plasma concentrations of mavacamten, EE, and NOR were obtained before dosing and up to 72 hours after dosing. For EE only, a physiologically based pharmacokinetic model was used to simulate mavacamten‐mediated CYP3A4 induction with EE for various CYP2C19 phenotypes. In total, 13 women were enrolled (mean age, 38.9 [standard deviation, 9.65] years). After mavacamten administration, modest increases in area under the concentration–time curves were observed for both EE and NOR. The maximum concentrations and half‐lives for EE and NOR were not affected by coadministration with mavacamten. Criteria for bioequivalence were met or nearly met for EE and NOR exposure with geometric mean ratios between 0.8 and 1.25. All adverse events were mild. The physiologically based pharmacokinetic model predicted a less than 15% decrease in EE exposure across CYP2C19 phenotypes. Coadministration of mavacamten at a therapeutically relevant dose with EE and NOR did not decrease the exposure to either EE or NOR to a level that may lead to reduced effectiveness. [ABSTRACT FROM AUTHOR]

The behavior of four drugs from the family of nucleoside analog reverse-transcriptase inhibitors (zalcitabine, stavudine, didanosine, and apricitabine) in a membrane environment was traced using molecular dynamics simulations. The simulation models included bilayers and monolayers composed of POPC and POPG phospholipids. It was demonstrated that the drugs have a higher affinity towards POPG membranes than POPC membranes due to attractive long-range electrostatic interactions. The results obtained for monolayers were consistent with those obtained for bilayers. The drugs accumulated in the phospholipid polar headgroup region. Two adsorption modes were distinguished. They differed in the degree of penetration of the hydrophilic headgroup region. Hydrogen bonds between drug molecules and phospholipid heads were responsible for adsorption. It was shown that apricitabine penetrated the hydrophilic part of the POPC and POPG membranes more effectively than the other drugs. Van der Waals interactions between S atoms and lipids were responsible for this. [ABSTRACT FROM AUTHOR]

The problem of dissipativity analysis is discussed for Lur'e systems with two additive time‐varying delays (ATDs) in this paper. Based on the dynamic delay interval (DDI) method, some novel Lyapunov‐Krasovskii functionals (LKFs) are constructed, in which part of Lyapunov matrices are requested to be positive definite. Then strictly dissipativity criteria of Lur'e systems with ATDs are presented in terms of linear matrix inequalities (LMIs). As by‐products, the stability criteria of Lur'e systems with ATDs and the systems with ATDs are derived. Finally, several numerical examples are used to illustrate the effectiveness and superiority of these criteria. [ABSTRACT FROM AUTHOR]

Background: Azvudine (FNC) is a promising treatment candidate for managing coronavirus disease 2019 (COVID-19). However, drug interactions with azvudine have been poorly studied, especially with no reported cases of azvudine with anticoagulants such as warfarin and rivaroxaban. Case summary: The patient was diagnosed with lower limb venous thrombosis and took warfarin regularly. The international normalized ratio (INR) was stable (2.0-3.0). However, the INR increased to 7.52 after administering azvudine. The patient had no other factors justifying this change. This increase in INR occurred again with the administration of azvudine in combination with rivaroxaban, and the INR increased to 18.91. After azvudine administration was stopped, the INR did not increase when rivaroxaban was used alone. Conclusion: Azvudine, warfarin, and rivaroxaban might have previously unidentified drug interactions that increased the INR. Therefore, the INR must be closely monitored when they are concomitantly administered in COVID-19 patients. [ABSTRACT FROM AUTHOR]

In recent years, the field of nephrology has been focusing on organ-organ or organ-disease interactions, among which it has become clear that cancer and psychiatric disorders or kidney disease mutually exacerbate pathological conditions. Onconephrology has developed in relation to cancer and kidney disease and psychonephrology in relation to cancer and neuropsychiatric disorders. On the other hand, these advances are accompanied by an increase in life expectancy and consequently an increase in the number of patients with chronic kidney disease (CKD). End-stage kidney disease (ESKD) patients requires renal replacement therapy. The age of patients on dialysis is getting older, and the initiation and maintenance of dialysis therapy are becoming more life-threatening. This article introduces the outline of these new concepts of psycho-onco-nephrology and conservative kidney management (CKM), and outlines drug-drug interactions and associated renal damage in CKD patients, who are frequently prescribed multiple drugs. [ABSTRACT FROM AUTHOR]

Background: Preclinical studies showed that capmatinib reversibly inhibits cytochrome P450 (CYP) 3A4 and CYP1A2 in a time‐dependent manner. In this study, we evaluated the effect of capmatinib on the exposure of sensitive substrates of CYP3A (midazolam) and CYP1A2 (caffeine) in patients with mesenchymal–epithelial transition (MET)‐dysregulated solid tumours. Besides pharmacokinetics, we assessed treatment response and safety. Methods: This open‐label, multicentre, single‐sequence study consisted of a molecular prescreening period, a screening/baseline period of ≤28 days and a drug‐drug interaction (DDI) phase of 12 days. On day 1 of the DDI phase, 37 patients received a single oral dose of midazolam 2.5 mg and caffeine 100 mg as a two‐drug cocktail. Capmatinib 400 mg bid was administered from day 4 on a continuous dosing schedule. On day 9 of the DDI phase, patients were re‐exposed to midazolam and caffeine. After the DDI phase, patients received capmatinib on continuous 21‐day cycles until disease progression at the discretion of the investigator. Results: A 22% (90% confidence interval [CI] 7‐38%) increase in the midazolam maximum plasma concentration (Cmax) was noted when administered with capmatinib, but this was deemed not clinically meaningful. Co‐administration with capmatinib resulted in 134% (90% CI 108‐163%) and 122% (90% CI 95‐153%) increases in the caffeine area under the plasma concentration‐time curve from time zero to infinity (AUCinf) and area under the plasma concentration‐time curve from time zero to the last measurable point (AUClast), respectively, with no change in Cmax. Adverse events were consistent with the known capmatinib safety profile. No new safety signals were reported in this study. Conclusion: The data from this study demonstrated that capmatinib is a moderate CYP1A2 inhibitor. Capmatinib administration did not cause any clinically relevant changes in midazolam exposure. [ABSTRACT FROM AUTHOR]

Mycotoxins such as aflatoxin B1 (AFB1) are secondary fungal metabolites present in food commodities and part of one's daily exposure, especially in certain regions, e.g., sub-Saharan Africa. AFB1 is mostly metabolised by cytochrome P450 (CYP) enzymes, namely, CYP1A2 and CYP3A4. As a consequence of chronic exposure, it is interesting to check for interactions with drugs taken concomitantly. A physiologically based pharmacokinetic (PBPK) model was developed based on the literature and in-house-generated in vitro data to characterise the pharmacokinetics (PK) of AFB1. The substrate file was used in different populations (Chinese, North European Caucasian and Black South African), provided by SimCYP® software (v21), to evaluate the impact of populations on AFB1 PK. The model's performance was verified against published human in vivo PK parameters, with AUC ratios and Cmax ratios being within the 0.5–2.0-fold range. Effects on AFB1 PK were observed with commonly prescribed drugs in South Africa, leading to clearance ratios of 0.54 to 4.13. The simulations revealed that CYP3A4/CYP1A2 inducer/inhibitor drugs might have an impact on AFB1 metabolism, altering exposure to carcinogenic metabolites. AFB1 did not have effects on the PK of drugs at representative exposure concentrations. Therefore, chronic AFB1 exposure is unlikely to impact the PK of drugs taken concomitantly. [ABSTRACT FROM AUTHOR]

Ming-Na Lu, Bai-Lei Zhang, Qiao-Hong Dai, Xian-Hu Fu Department of Obstetrics and Gynecology, Ningbo Women and Children’s Hospital, Ningbo, 315012, People’s Republic of ChinaCorrespondence: Qiao-Hong Dai, Department of Obstetrics and Gynecology, Ningbo Women and Children’s Hospital, Ningbo, 315012, People’s Republic of China, Tel +86 13858220557, Email daiqiaohongdqh@126.comObjective: To discuss the application value of the plan–do–check–act (PDCA) cycle in shortening the decision to delivery interval (DDI) time.Methods: A total of 106 DDI cases from the Ningbo Women and Children’s Hospital (China) from January 2019 to December 2020 were selected as the subjects of this study. The causes for the prolongation of DDI were analyzed and protocols were developed. Through continuous summaries and improvement, a standardized process was established to direct clinical application, ie, the PDCA cycle.Results: The DDI was shortened from 14.26 min in 2019 to 12.18 min in 2020 and the neonatal asphyxia rate significantly decreased from 34.69% in 2019 to 12.50% in 2020 (P < 0.05).Conclusion: The PDCA cycle management mode effectively shortened the DDI time and reduced the neonatal asphyxia rate, without increasing adverse maternal outcomes.Keywords: PDCA cycle, emergency C-delivery, DDI, neonatal, asphyxia

Mechanical characterization usually relies on standardized sample geometries where homogeneous state of strain and stress are prescribed. Hence, many tests are required to capture the material response over various loading conditions. Using complex geometry allows for exploring wider domain in a single test but would require to have access to local strains and stresses to feed models. In that context, digital image correlation and clustering technique can be used to formulate an inverse problem able to identify fields of stress tensors without a priori constitutive modelling. This study explores the performances of a rate-dependent formulation of such a data-driven stress identification method, for capturing using a single test, the monotonic high strain-rate dependent response of a mild steel alloy. After presenting the problem formulation and resolution framework, a digital twin of a high speed tensile test performed on a notched sample geometry is used to explore identification performances. It allows defining confidence intervals depending on multiple indicators (stress magnitude, multiaxiality) and evaluate the range of strain-rate levels simultaneously captured. The method is eventually applied to a real experiment instrumented with high spatial resolution ultra high speed camera. Stress tensor fields are identified, within a 10 % confidence over the major part of the sample, and its material rate-dependence is retrieved from 20 to 300 s−1 and found in very good agreement with literature. This is the first experimental application of the DDI in a high strain-rate context. The proposed framework may substantially widen the sample design space for mechanical characterization but also allow for probing local stresses during dynamic localization processes where in-situ quantitative data are still missing. • A Rate-dependent formulation of DDI is numerically and experimentally assessed. • Stress fields are identified within 11% error beyond 100 MPa. • The monotonic high strain-rate dependent response of a mild steel is captured. • The yield stress and stress flow rate-dependence is identified up to 300 s-1. [ABSTRACT FROM AUTHOR]

Organ transplantation is associated with significant physical and psychological burden for the recipients. Qualitative reports indicate that organ recipients develop donor and donation images (DDI)—conceptions of the donor and/or the organ. A deeper understanding of DDI is needed in the care of transplant recipients. To present the current state of knowledge, we searched for and identified DDI-related publications in PubMed and Scopus. Inclusion criteria were (1) studies addressing transplant recipients, and (2) English or German language. Twenty-one studies of individuals with transplanted hearts, lungs, or kidneys were included in this scoping review. Prevalence for DDI ranged from 6% to 52.3%. DDI occurs both before and after transplantation and includes ideas about the donor as well as whether and how the recipient's personality may be altered by the transplanted organ. Some transplant recipients did indeed report personality changes following transplantation due to the adoption of assumed donor characteristics. One study showed a positive association between the presence of DDI and anxiety scores and one described a coping effect. DDI is understudied and should be systematically assessed to improve care for the vulnerable group of individuals undergoing organ transplantation. Current research gaps and future directions are discussed. [ABSTRACT FROM AUTHOR]

BTK inhibitor exposure increases significantly when coadministered with CYP3A inhibitors, which may lead to dose-related toxicities. This study explored the pharmacokinetics, efficacy, and safety of zanubrutinib when coadministered with moderate or strong CYP3A inhibitors in 26 patients with relapsed or refractory B-cell malignancies. Coadministration of zanubrutinib (80 mg BID) with moderate CYP3A inhibitors fluconazole and diltiazem or zanubrutinib (80 mg QD) with strong CYP3A inhibitor voriconazole resulted in comparable exposures to zanubrutinib (320 mg QD) with AUC0-24h geometric least squares mean ratios approaching 1 (0.94, 0.81, and 0.83, for fluconazole, diltiazem, and voriconazole, respectively). The most common treatment-emergent adverse events were contusion (26.9%), back pain (19.2%), constipation and neutropenia (15.4% each), and rash, diarrhea, and fall (11.5% each). This study supports current United States Prescribing Information dose recommendations for the coadministration of reduced-dose zanubrutinib with moderate or strong CYP3A inhibitors and confirms the favorable efficacy and safety profile of zanubrutinib. [ABSTRACT FROM AUTHOR]

An extraction of significant information from Internet sources is an important task of pharmacovigilance due to the need for post-clinical drugs monitoring. This research considers the task of end-to-end recognition of pharmaceutically significant named entities and their relations in texts in natural language. The meaning of "end-to-end" is that both of the tasks are performed within a single process on the "raw" text without annotation. The study is based on the current version of the Russian Drug Review Corpus—a dataset of 3800 review texts from the Russian segment of the Internet. Currently, this is the only corpus in the Russian language appropriate for research of the mentioned type. We estimated the accuracy of the recognition of the pharmaceutically significant entities and their relations in two approaches based on neural-network language models. The first core approach is to sequentially solve tasks of named-entities recognition and relation extraction (the sequential approach). The second one solves both tasks simultaneously with a single neural network (the joint approach). The study includes a comparison of both approaches, along with the hyperparameters selection to maximize resulting accuracy. It is shown that both approaches solve the target task at the same level of accuracy: 52–53% macro-averaged F 1 - s c o r e , which is the current level of accuracy for "end-to-end" tasks on the Russian language. Additionally, the paper presents the results for English open datasets ADE and DDI based on the joint approach, and hyperparameter selection for the modern domain-specific language models. The result is that the achieved accuracies of 84.2% (ADE) and 73.3% (DDI) are comparable or better than other published results for the datasets. [ABSTRACT FROM AUTHOR]

Ensuring safe and comfortable conditions for pedestrians necessitates specific strategies at intersections and service interchanges where traffic and pedestrians interact in complex ways with other modes of transportation. This study aims to investigate pedestrian performance at the new Super Diverging Diamond Interchange (Super DDI) using real-world locations (i.e., I-225 and Mississippi Ave, I-25 and 120th Ave, and I-25 and Hampden Ave in Denver, Colorado). Three alternative designs, typical DDI, and two versions of Super DDI were considered to make a reasonable comparison with the existing Conventional Diamond Interchange (CDI). A comprehensive series of simulation models (192 scenarios with 960 runs) were tested using VISSIM and Synchro to analyze pedestrian operation (travel time, number of stops, and waiting time) in various traffic and pedestrian distributions. As one of the primary contributions in this paper, pedestrian safety was evaluated based on a surrogate performance measure called design flag, introduced by the new National Cooperative Highway Research Program (NCHRP-948) guideline. The results indicated that the proposed new Super DDI designs are relatively safe when compared with CDI and DDI. For example, a pedestrian analysis of one of the most popular alternative interchanges, DDI, showed potential for unsafe pedestrian conditions in all aspects. [ABSTRACT FROM AUTHOR]

The aim of the present study is to reflect on the experiences of emergency didactics, distance education (DAD) and digitally integrated education (DDI), of primary school teachers on a regional scale (Veneto), in terms of resilience display. Several teachers answered an online questionnaire at two points in time: at the time of DaD (spring 2020 – N=494) and when DDI became more widespread (winter 2021-2022 – N=620). The participants showed resilience when facing the Covid-19 crisis: the school system resisted, albeit mostly by implementing traditional teaching set-ups, especially through DaD. Two protective factors for resilience were explored: collaboration and technological training. Their impact as protective factors on the development of teachers’ resilience proved not decisive, although slight improvements are noted between the two survey datasets. Didattiche emergenziali a confronto: collaborazione e formazione tecnologica per lo sviluppo di resilienza negli insegnanti. L’obiettivo del presente studio è quello di offrire una rilettura sulle esperienze di didattica emergenziale, Didattica a Distanza (DAD) e Didattica Digitale Integrata (DDI), vissute da insegnanti di scuola primaria su scala regionale (Veneto) in chiave di manifestazione di capacità di resilienza. Svariati insegnanti hanno risposto ad un questionario online in due momenti: al tempo della DaD (primavera 2020 – N=494) e quando la DDI si è diffusa maggiormente (inverno 2021-2022 – N=620). I partecipanti hanno manifestato capacità di resilienza di fronte alla crisi Covid-19: il sistema scuola è resistito, seppur implementando assetti didattici di tipo tradizionale, specie in DaD. Si sono approfonditi due fattori protettivi per la resilienza: la collaborazione e la formazione tecnologica. Rispetto al loro impatto sullo sviluppo delle capacità di resilienza degli insegnanti, sebbene si notino deboli miglioramenti tra le due rilevazioni, i dati mostrano che essi non possono essere considerati fattori protettivi particolarmente determinanti.

Copyright of Form@re is the property of Firenze University Press 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.)

Plasma concentrations of direct oral anticoagulants (DOAC) are potentially affected because of drug-drug interactions (DDI) with anticancer treatment as a result of inhibition or induction of CYP3A4, p-glycoprotein (P-gp) and/or Breast Cancer Resistance Protein (BCRP) interactions.Here, we present a 78-year-old patient with non-small cell lung cancer (NSCLC) receiving treatment with alectinib concurrent with apixaban as prophylactic treatment of recurrent thrombophlebitis. Given the unexpected high apixaban plasma concentrations, the apixaban dose was reduced stepwise to 25% of its original dose in order to achieve values within the on-therapy reference range. This case demonstrates that monitoring DOAC plasma concentrations may be indicated when DOACs are used concurrently with alectinib.

Purpose: Venetoclax (VEN), an anti-tumor drug that is a substrate of cytochrome P450 3A enzyme (CYP3A4), is used to treat leukemia. Voriconazole (VCZ) is an antifungal medication that inhibits CYP3A4. The goal of this study is to predict the effect of VCZ on VEN exposure. Method: Two physiological based pharmacokinetics (PBPK) models were developed for VCZ and VEN using the bottom-up and top-down method. VCZ model was also developed to describe the effect of CYP2C19 polymorphism on its pharmacokinetics (PK). The reversible inhibition constant (Ki) of VCZ for CYP3A4 was calibrated using drug-drug interaction (DDI) data of midazolam and VCZ. The clinical verified VCZ and VEN model were used to predict the DDI of VCZ and VEN at clinical dosing scenario. Result: VCZ model predicted VCZ exposure in the subjects of different CYP2C19 genotype and DDI related fold changes of sensitive CYP3A substrate with acceptable prediction error. VEN model can capture PK of VEN with acceptable prediction error. The DDI PBPK model predicted that VCZ increased the exposure of VEN by 4.5–9.6 fold. The increase in VEN exposure by VCZ was influenced by subject's CYP2C19 genotype. According to the therapeutic window, VEN dose should be reduced to 100 mg when co-administered with VCZ. Conclusion: The PBPK model developed here could support individual dose adjustment of VEN and DDI risk assessment. Predictions using the robust PBPK model confirmed that the 100 mg dose adjustment is still applicable in the presence of VCZ with high inter-individual viability. [ABSTRACT FROM AUTHOR]

Imipenem (IMP) possesses a broad spectrum of antibacterial activity; however, nephrotoxicity limits its clinical application in patients with renal insufficiency. In our previous studies, a dipeptide, JBP485, a dipeptide with the chemical structure cyclo-trans-4-L-hydroxyprolyl-L-serine, was found to attenuate drug-induced kidney injury. The current study aimed to explore whether JBP485 could relieve IMP-induced kidney injury and clarify the potential molecular pharmacokinetic mechanism. The effects of JBP485 on IMP nephrotoxicity were evaluated in rabbits and human kidney 2 (HK-2) cells. Drug-drug interactions (DDIs) mediated by organic anion transporters (OATs) and dehydropeptidase-I (DHP-I) were explored through pharmacokinetic studies in rats, metabolism assays in the kidney, and uptake studies in OAT-over-expressing cells. The results revealed that JBP485 significantly ameliorated IMP-induced nephrotoxicity in rabbits. Further, incubation of HK-2 cells with JBP485 or cilastatin markedly improved the cell survival rate, inhibited apoptosis and attenuated mitochondrial damage by improving the stability of IMP and reducing its intracellular accumulation. This suggests that DHP-I and OATs might be involved in the protective effect of JBP485. Furthermore, coadministration with JBP485 significantly increased the IMP's plasma concentration as well as the area under the plasma concentration-time curve (AUC), while decreasing IMP renal clearance and cumulative urinary excretion. Moreover, JBP485 reduced IMP uptake in kidney slices and OAT1/3-human embryonic kidney 293 (HEK293) cells. At the same time, the metabolism of IMP by DHP-I was inhibited by JBP485 with an IC50 value of 12.15 ± 1.22 μM. Finally, the molecular docking assay revealed a direct interaction between JBP485 and OAT1/3 or DHP-I. In conclusion, JBP485 protected against IMP nephrotoxicity in rabbits and HK-2 cells by improving IMP stability and reducing its intracellular accumulation via simultaneous inhibition of renal OATs and DHP-I. JBP485 is a promising renoprotective agent and could serve as an effective supplement to reduce IMP-induced adverse renal reactions in the clinical setting. [ABSTRACT FROM AUTHOR]

Research in Artificial Intelligence has helped to achieve significant progress during the last decade, in various sectors. As concern agriculture, tomato is one of the most cultivated and consumed vegetables in the world because of its nutritional and therapeutic properties. However, this crop faces phytosanitary problems. This study contributes to the automatic Disease Detection and Identification (DDI) in tomato plants using neural networks. The proposed model performs the DDI of tomato from the images of tomato leaves or the videos from cameras installed in the plantation. The extraction of the tomato leaves images in the video was done using object recognition by RGB color. We extract the features from the images using transfer learning based on the pre-trained ResNet101 and ResNet152 models, and their classification is done by the multi-layer perceptron. To obtain better accuracy, the characteristics of our images were extracted at several levels from the pre-trained model. We observed that the recognition rate increased with the number of layers except for the last layer for which the accuracy was low. It was also observed that the replacement of the input vectors by the distance from the mean improved the results obtained in the literature. As a result of this work, we obtained an accuracy of 97.26% and 97.5% from transfer learning of the two pre-trained architectures and we improve these state-of-art results to 98.3% using fivefold with the concatenation of two mean deviation features extracted from ResNet101 and ResNet152. In terms of maximum accuracy, we obtained 98.9%. These results will be used to calibrate the automatic mobile camera system moving on rails. [ABSTRACT FROM AUTHOR]

Abstract Background A hospitalization phase represents a challenge to medication safety especially for multimorbid patients as acute medical needs might interact with pre-existing medications or evoke adverse drug effects. This project aimed to examine the prevalence and risk factors of potentially inappropriate medications (PIMs) and medication combinations (PIMCs) in the context of hospitalizations. Methods Analyses are based on claims data of patients (≥65 years) with basic mandatory health insurance at the Helsana Group, and on data from the Hirslanden Swiss Hospital Group. We assessed PIMs and PIMCs of patients who were hospitalized in 2013 at three different time points (quarter prior, during, after hospitalization). PIMs were identified using the PRISCUS list, whereas PIMCs were derived from compendium.ch. Zero-inflated Poisson regression models were applied to determine risk factors of PIMs and PIMCs. Results Throughout the observation period, more than 80% of patients had at least one PIM, ranging from 49.7% in the pre-hospitalization, 53.6% in the hospitalization to 48.2% in the post-hospitalization period. PIMCs were found in 46.6% of patients prior to hospitalization, in 21.3% during hospitalization, and in 25.0% of patients after discharge. Additional medication prescriptions compared to the preceding period and increasing age were the main risk factors, whereas managed care was associated with a decrease in PIMs and PIMCs. Conclusion We conclude that a patient’s hospitalization offers the possibility to increase medication safety. Nevertheless, the prevalence of PIMs and PIMCs is relatively high in the study population. Therefore, our results indicate a need for interventions to increase medication safety in the Swiss healthcare setting.

Imipenem (IMP) possesses a broad spectrum of antibacterial activity; however, nephrotoxicity limits its clinical application in patients with renal insufficiency. In our previous studies, a dipeptide, JBP485, a dipeptide with the chemical structure cyclo-trans-4-L-hydroxyprolyl-L-serine, was found to attenuate drug-induced kidney injury. The current study aimed to explore whether JBP485 could relieve IMP-induced kidney injury and clarify the potential molecular pharmacokinetic mechanism. The effects of JBP485 on IMP nephrotoxicity were evaluated in rabbits and human kidney 2 (HK-2) cells. Drug-drug interactions (DDIs) mediated by organic anion transporters (OATs) and dehydropeptidase-I (DHP-I) were explored through pharmacokinetic studies in rats, metabolism assays in the kidney, and uptake studies in OAT-over-expressing cells. The results revealed that JBP485 significantly ameliorated IMP-induced nephrotoxicity in rabbits. Further, incubation of HK-2 cells with JBP485 or cilastatin markedly improved the cell survival rate, inhibited apoptosis and attenuated mitochondrial damage by improving the stability of IMP and reducing its intracellular accumulation. This suggests that DHP-I and OATs might be involved in the protective effect of JBP485. Furthermore, coadministration with JBP485 significantly increased the IMP’s plasma concentration as well as the area under the plasma concentration-time curve (AUC), while decreasing IMP renal clearance and cumulative urinary excretion. Moreover, JBP485 reduced IMP uptake in kidney slices and OAT1/3-human embryonic kidney 293 (HEK293) cells. At the same time, the metabolism of IMP by DHP-I was inhibited by JBP485 with an IC50 value of 12.15 ± 1.22 μM. Finally, the molecular docking assay revealed a direct interaction between JBP485 and OAT1/3 or DHP-I. In conclusion, JBP485 protected against IMP nephrotoxicity in rabbits and HK-2 cells by improving IMP stability and reducing its intracellular accumulation via simultaneous inhibition of renal OATs and DHP-I. JBP485 is a promising renoprotective agent and could serve as an effective supplement to reduce IMP-induced adverse renal reactions in the clinical setting.