215,807 results on '"DRUG interactions"'
Search Results
2. Shared Decision for Drug Interactions in Oral Anticoagulation (DDInteract)
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Agency for Healthcare Research and Quality (AHRQ) and Daniel Malone, Professor
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- 2024
3. Cytochrome P450 inhibitor/inducer treatment patterns among patients in the United States with advanced ovarian cancer who were prescribed or were eligible for poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors in the first-line maintenance setting.
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Perhanidis, Jessica, Ghazarian, Armen, Du, Ella, Wang, Travis, Song, Jinlin, Golembesky, Amanda, Hurteau, Jean, Kalilani, Linda, Salani, Ritu, Monk, Bradley, Rimel, Bobbie, and Chase, Dana
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Advanced ovarian cancer ,CYP450 inhibitor/inducer ,Drug interactions ,Poly(ADP ribose) polymerase inhibition - Abstract
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.
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- 2024
4. Drug-Drug Interaction Study of Pacritinib and CYP450,Transporter Substrates, and CYP450 3A4 in Healthy Male Subjects
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PPD
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- 2024
5. In vitro antifungal activity of eucalyptol and its interaction with antifungal drugs against clinical dermatophyte isolates including Trichophyton indotineae.
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Ghazi Mirsaid, Romina, Falahati, Mehraban, Farahyar, Shirin, Ghasemi, Zeinab, Roudbary, Maryam, and Mahmoudi, Shahram
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ANTIBIOTICS , *THERAPEUTIC use of essential oils , *EUCALYPTUS oil , *ANTIFUNGAL agents , *IN vitro studies , *MYCOSES , *BAR codes , *COMBINATION drug therapy , *RINGWORM , *DIAGNOSTIC imaging , *RESEARCH funding , *MICROBIAL sensitivity tests , *DERMATOLOGY , *POLYMERASE chain reaction , *ITRACONAZOLE , *TERTIARY care , *NAILS (Anatomy) , *DISEASE prevalence , *SKIN , *GRISEOFULVIN , *PLANT extracts , *DRUG interactions , *PHENOLS , *MEDICINAL plants , *HAIR , *MICROSCOPY , *TERBINAFINE , *DISEASE susceptibility , *DERMATOMYCOSES , *MOLECULAR diagnosis , *BIOMARKERS , *DRUG resistance , *PHARMACODYNAMICS - Abstract
Background: Dermatophytosis, a prevalent fungal infection, often exhibits treatment failure. It poses ongoing public health concerns, urging exploration of alternative treatment strategies. This study examines eucalyptol's in vitro activity and its interaction with antifungal agents against dermatophyte isolates. Methods: Overall, 489 patients clinically suspected of dermatophytosis were investigated, and the causative agents were molecularly identified. The antifungal activity of eucalyptol, itraconazole, terbinafine, and griseofulvin was assessed according to the guideline of the Clinical and Laboratory Standards Institute (CLSI M38 ed3). The interaction between eucalyptol and the aforementioned antifungals was determined using a checkerboard method. Results: Dermatophytosis was confirmed in 30 out of 489 (6.13%) patients, with a female-to-male ratio of 3:2 and an age range of 8–67 years. The most commonly observed clinical manifestation was tinea corporis (34.21%), and Trichophyton indotineae (n = 14, 46%) was the most common causative agent. Antifungal susceptibility testing revealed that eucalyptol exhibited antidermatophyte properties with minimum inhibitory concentrations (MIC) ranging from 0.78 to 25 mg/mL. Itraconazole demonstrated the lowest geometric mean (GM) value (MIC range: 0.0019–0.25 µg/mL, GM: 0.015 µg/mL), while griseofulvin exhibited the highest GM value (MIC range: 0.125–8 µg/mL, GM: 2.37 µg/mL). The in vitro interaction of eucalyptol with antifungal drugs, except for its combination with terbinafine against two Trichophyton tonsurans isolates resulting in synergistic effects, showed indifference (n = 70, 77.77%) and antagonistic types (n = 18, 20%). Conclusion: Among the evaluated antifungals, itraconazole demonstrated the highest effectiveness against clinical isolates, while eucalyptol alone exhibited a more pronounced effect than when combined with antifungal agents. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Clinical, pharmacological, and qualitative characterization of drug–drug interactions in pregnant women initiating HIV therapy in Sub-Saharan Africa.
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Kiiza, Daniel, Rostami-Hochaghan, Danial, Alhassan, Yussif, Seden, Kay, Reynolds, Helen, Kaboggoza, Julian P, Taegtmeyer, Miriam, Chen, Tao, Challenger, Elizabeth, Malaba, Thokozile, Wang, Duolao, Else, Laura, Hern, Faye, Sharp, Jo, Neary, Megan, Penchala, Sujan Dilly, Waitt, Catriona, Orrell, Catherine, Colbers, Angela, and Myer, Landon
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Background We investigated the impact of Drug–Drug Interactions (DDIs) on virologic control among HIV-positive pregnant women initiating antiretroviral therapy while identifying drivers for Traditional Medicine (TM) use and exploring the nature and extent of TM-related DDIs. Methods Employing a three-pronged approach, we examined DDIs arising from comedication, including TM, in ART. The DolPHIN-2 trial (NCT03249181) randomized 268 HIV-positive pregnant women in Uganda and South Africa to dolutegravir (DTG)-based (135) or efavirenz-based (133) regimens while systematically recording comedications and screening for DDIs. We used Cox regression models to compare time-to-virologic control between participants with and without DDIs. We conducted in-depth interviews and focus group discussions among 37 and 67 women with and without HIV, respectively, to explore reasons for TM use during pregnancy. Additionally, in-vitro and in-vivo studies evaluated the composition and impact of clay-based TM, mumbwa , on DTG plasma exposure. Results The baseline prevalence of DDIs was 67.2%, with TM use prevalent in 34% of participants, with mumbwa being the most frequent (76%, 69/91). There was no difference in virologic response between participants with and without DDIs. Fetal health and cultural norms were among the reasons cited for TM use. Analysis of mumbwa rods confirmed significant amounts of aluminium (8.4%–13.9%) and iron (4%–6%). In Balb-C mice, coadministration of mumbwa led to a reduction in DTG exposure observed in the AUC0-24 (−21%; P = 0.0271) and C24 (−53%; P = 0.0028). Conclusions The widespread use of clay-based TM may compromise HIV treatment, necessitating medication screening and counselling to manage DDIs in pregnant women. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Polypharmacy, anticholinergic burden and drug–drug interaction assessment in people with four-class-resistant HIV: data from the PRESTIGIO registry.
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Mazzitelli, Maria, Pontillo, Domenico, Clemente, Tommaso, Biagio, Antonio Di, Cenderello, Giovanni, Rusconi, Stefano, Menzaghi, Barbara, Fornabaio, Chiara, Garlassi, Elisa, Zazzi, Maurizio, Castagna, Antonella, Cattelan, Anna Maria, and Group, PRESTIGIO Study
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Objectives To evaluate polypharmacy, anticholinergic burden (ACB) and drug–drug interactions (DDIs) in people with four-class-resistant HIV (4DR-PWH). Methods We performed a cross-sectional study, including 4DR-PWH from the PRESTIGIO Registry taking at least one non-antiretroviral drug. Polypharmacy was defined as taking five or more non-antiretroviral drugs. ACB was calculated using the ACB scale: 0 = no AC effect, 1–2 = low/moderate risk, ≥3 = high AC risk. Participants' characteristics by ACB score were compared using the Kruskal–Wallis test, and Spearman's correlation coefficient was used to assess linear relationships. DDIs were evaluated using the Liverpool database. Results Overall, 172 4DR-PLWH were evaluated: 75.6% males, median age 49.9 years (IQR = 45.6–56), 62 (27.1%) on polypharmacy, 124 (72.1%) using a boosting agent and 72 (41.8%) with four or more antiretrovirals. Based on ACB, 128 (74.45%), 33 (19.2%) and 11 (6.4%) had a no, low/moderate and high AC risk, respectively. The most common AC drugs were β-blockers (12.2%), diuretics (8.7%) and antidepressants (8.7%). The high ACB was significantly related to the number of drugs/person (r = 0.33, P < 0.0001) and the number of clinical events (r = 0.222, P = 0.004). Overall, 258 DDIs were found between antiretrovirals and co-medications in 115 (66.8%) PWH, and 14 (8.1%) PWH received contraindicated drug combinations. Conclusions In 4DR-PWH, polypharmacy, DDIs and the proportion of people with moderate/high AC burden were high. In 4DR-PWH undetectability achievement and maintenance is the priority and use of boosted PIs is common. A strict collaboration (infectious diseases specialists, virologists, pharmacologists) is needed to limit the risk of ACB and DDIs and to explore the advantages of new antiretrovirals. [ABSTRACT FROM AUTHOR]
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- 2024
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8. CYP3A4 inhibitors may influence the quantification of [123I]I-FP-CIT SPECT scans.
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Booij, Jan, Yağci, Eda, Sheikh, Zulfiqar H, and Chahid, Youssef
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Purpose: [123I]I-FP-CIT SPECT is an imaging tool to support the diagnosis of parkinsonian syndromes characterized by nigrostriatal dopaminergic degeneration. After intravenous injection, [123I]I-FP-CIT is metabolized for a small part by the enzyme CYP3A4, leading to the formation of [123I]I-nor-β-CIT. [123I]I-nor-β-CIT passes the blood-brain barrier and has a very high affinity for the serotonin transporter (SERT). The SERT is expressed in the striatum and cortical areas. So, at least theoretical, the use of frequently used CYP3A4 inhibitors (like amiodarone) may influence the specific to non-specific striatal [123I]I-FP-CIT ratio. Here we tested this novel hypothesis. Methods: Using a retrospective design, we determined the specific to non-specific striatal [123I]I-FP-CIT ratio (using BRASS software) in 6 subjects that were using an CYP3A4 inhibitor and 18 matched controls. Only subjects were included with a normal rated [123I]I-FP-CIT SPECT scan, and all participants were scanned on the same brain-dedicated SPECT system. Results: The specific to non-specific (assessed in the occipital cortex) striatal [123I]I-FP-CIT binding ratio was significantly higher in CYP3A4 users than in the control group (3.52 ± 0.33 vs. 2.90 ± 0.78, p < 0.001). Conclusion: Our preliminary data suggest that the use of CYP3A4 inhibitors may influence striatal [123I]I-FP-CIT binding ratios. This information, when reproduced in larger studies, may be relevant for studies in which quantification of [123I]I-FP-CIT SPECT imaging is used for diagnostic or research purposes. [ABSTRACT FROM AUTHOR]
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- 2024
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9. Clinical Implications of Co‐administering Apixaban with Key Interacting Medications.
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Favatella, Nicholas, Dalton, David, Byon, Wonkyung, Merali, Samira J., and Klem, Christian
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With many available data sources, clinicians need to consider the benefit‐risk profile of individual anticoagulants when balancing the need for anticoagulation, including evaluating the risks in patients with comorbidities and potential drug‐drug interactions. This narrative review presents clinical data across multiple phases of drug development for the use of apixaban, a selective factor Xa inhibitor, when taken concomitantly with other agents, and evaluates the benefit‐risk profile of apixaban with these interacting medications. Key subgroup analyses from the phase 3 ARISTOTLE trial (NCT00412984) are presented using data from patients who received either concomitant inhibitors or inducers of cytochrome P450 3A4 and/or P‑glycoprotein. We also review the available evidence for the use of apixaban in patients with cancer‐associated thromboembolism, as well as the use of apixaban in patients with COVID‐19. [ABSTRACT FROM AUTHOR]
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- 2024
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10. DFT study on the Ciclopirox anticancer drug interaction with AlN nanostructures: analysed by AIM, UV-Vis and Marcus theory of electron-transfer.
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Saadh, Mohamed J., Sánchez Herrera, Tatiana Elizabeth, Mohammed Dhiaa, Aya, Villacrés Cáceres, Oswaldo, Flores Fiallos, Linda Mariuxi, Rojas Oviedo, Byron Stalin, Omran, Alaa A., Hawas, Majli Nema, and Elawady, Ahmed
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DENSITY functional theory , *CHEMICAL detectors , *ENERGY bands , *ELECTRIC conductivity , *DRUG interactions - Abstract
This study's main focus was on the process by which Ciclopirox adhered to AlN nanostructures, Calculations using the density functional theory were done to reach this goal. The calculations encompassed the assessment of Ciclopirox's adsorption energy, the evaluation of the energy band gap, the analysis of variations in the energy band gap, the examination of charge transfers, and the characterisation of the types of interactions that arise from Ciclopirox's adsorption onto AlN nanostructures. We carried out an investigation using the AIM method to explore deeper into the binding properties between the studied AlN nanostructures and Ciclopirox. Our discoveries provide light on the Ciclopirox/AlN nanosheet interaction's electrostatic characteristics. Moreover, the presence of Ciclopirox led to an augmentation in the electrical conductivity of the AlN nanostructures. This intriguing outcome suggests the potential application of these AlN nanomaterials as chemical sensors, capable of generating an electronic signal upon detection of this chemically modified amino acid. The observed sensitivity sequence indicated that the AlN nanosheet exhibited the highest sensitivity, followed by the AlN nanotube and the AlN nanocluster. In conclusion, our study provides compelling evidence supporting the AlN nanosheet as an excellent choice for the detection of Ciclopirox compared to other AlN nanostructures. [ABSTRACT FROM AUTHOR]
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- 2024
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11. COVID‐19 severity gradient differentially dysregulates clinically relevant drug processing genes in nasopharyngeal swab samples.
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Nwabufo, Chukwunonso K., Luc, Jessica, McGeer, Allison, Hirota, Jeremy Alexander, Mubareka, Samira, Doxey, Andrew C., and Moraes, Theo J.
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REGULATOR genes , *GENE expression , *MEMBRANE transport proteins , *DRUG metabolism , *DRUG interactions - Abstract
Aim: Understanding how COVID‐19 impacts the expression of clinically relevant drug metabolizing enzymes and membrane transporters (DMETs) is vital for addressing potential safety and efficacy concerns related to systemic and peripheral drug concentrations. This study investigates the impact of COVID‐19 severity on DMETs expression and the underlying mechanisms to inform the design of precise clinical dosing regimens for affected patients. Methods: Transcriptomics analysis of 102 DMETs, 10 inflammatory markers, and 12 xenosensing regulatory genes was conducted on nasopharyngeal swabs from 50 SARS‐CoV‐2 positive (17 outpatients, 16 non‐ICU, and 17 ICU) and 13 SARS‐CoV‐2 negative individuals, clinically tested through qPCR, in the Greater Toronto area from October 2020 to October 2021. Results: We observed a significant differential gene expression for 42 DMETs, 6 inflammatory markers, and 9 xenosensing regulatory genes. COVID‐19 severity was associated with the upregulation of AKR1C1, MGST1, and SULT1E1, and downregulation of ABCC10, CYP3A43, and SLC29A4 expressions. Altogether, SARS‐CoV‐2‐positive patients showed an upregulation in CYP2C9, CYP2C19, AKR1C1, SULT1B1, SULT2B1, and SLCO4A1 and downregulation in FMO5, MGST3, ABCC5, and SLCO4C1 compared with SARS‐CoV‐2 negative individuals. These dysregulations were associated with significant changes in the expression of inflammatory and xenosensing regulatory genes driven by the disease. GSTM3, PPARA, and AKR1C1 are potential biomarkers of the observed DMETs dysregulation pattern in nasopharyngeal swabs of outpatients, non‐ICU, and ICU patients, respectively. Conclusion: The severity of COVID‐19 is associated with the dysregulation of DMETs involved in processing commonly prescribed drugs, suggesting potential disease–drug interactions, especially for narrow therapeutic index drugs. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Formulation and Evaluation of Ciprofloxacin Ethosomal Gel for Microbial Infections.
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Rai, Roshni and Yadav, Ritesh
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CIPROFLOXACIN , *TOPICAL drug administration , *POLYETHYLENE glycol , *DRUG interactions , *BACTERIAL diseases , *MICROSCOPY , *MUPIROCIN - Abstract
The present study is to develop and evaluate an ethosomal gel formulation of ciprofloxacin. It aims to provide a topical treatment for many bacterial infections that affect the skin. Administration of medications topically having the facility of delivering a high concentration of the drug to the skin than would be possible with systemic therapy. Topical administration of drugs is better for local action and the efficiency of the topically administered drug is increased with liposome, proliposomes and ethosomes. Recently, it was found that ethosomal carriers were phospholipid vesicular systems having relatively high concentrations of alcohol, enhances dermal and transdermal delivery of both lipophilic as well as hydrophilic molecules. Ciprofloxacin hydrochloride is a second-generation antibiotic and a BCS class II drug. Ethosomes were formulated using phospholipid, cholesterol, ethanol, polyethylene glycol and purified water by cold method. Ethosomes were evaluated for vesicle size, shape, optical microscopy, entrapment efficiency and in-vitro release study. F4 have better drug entrapment efficiency than the other formulation. The best formulation (F4) was used to prepare gel by using carbopol 934 as a gelling agent. The ethosomes were entrapped in gel matrix of carbopol 980 in different concentration 0.5%, 1.00% and 2% w/w. FT-IR studies revealed no interaction between the drug and excipients. The formulated gel formulation was evaluated with parameter pH, viscosity, spreadability, in-vitro release test, wash ability, extrudability study and stability studies. The formulation EGF2 have better in-vitro drug release profile which contains carbopol 980 concentration 1%w/w. the stability studies performed (EGF2) at refrigeration temperature (4.0±0.2°C), at room temperature (25-28±2°C) and 45±1°C for 45days. These ethosomes were unstable at higher temperature like 45.2°C. Percent efficiency of ethosomes also decrease at higher temperature like 4502°C. The present work also focuses on making the formulation more pharmaceutically acceptable. [ABSTRACT FROM AUTHOR]
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- 2024
13. Value of Assessing 1‐Hydroxymidazolam in Drug‐Drug Interaction Studies with Midazolam as a Substrate of Cytochrome P450 3A.
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Magliocca, Massimo, Berger, Benjamin, Lemoine, Vincent, Kaufmann, Priska, and Dingemanse, Jasper
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INVESTIGATIONAL drugs , *MIDAZOLAM , *ORAL drug administration , *DRUG interactions , *CYTOCHROME P-450 - Abstract
The purpose of this overview was to perform an exploratory analysis of in‐house drug‐drug interaction (DDI) studies conducted with investigational drugs and oral midazolam to assess the value of measuring 1‐OH‐midazolam (1‐OHM) in such studies. The perpetrator effect of the investigational drugs on cytochrome P450 3A (CYP3A) was assessed by analyzing both midazolam and 1‐OHM in plasma and evaluating their pharmacokinetic parameters. Given the almost exclusive metabolism of the parent drug by CYP3A to the main metabolite 1‐OHM, an increase in midazolam and a decrease in 1‐OHM exposure in the case of CYP3A inhibition caused by a perpetrator drug would be expected. The opposite would be anticipated in the case of CYP3A induction. For this analysis, the perpetrator potential of eight different investigational drugs was incorporated. Among the 10 studies included, the identified CYP3A inhibitors (n = 4) and inducers (n = 1) were classified based on the data generated with midazolam per se, with 1‐OHM levels not contributing to the interpretation of the data as they did not corroborate the findings of the parent compound. Therefore, it was concluded that continued analysis of 1‐OHM in plasma may be questionable as it does not add value to the interpretation of the results when performing CYP3A DDI studies with an investigational drug as a perpetrator. [ABSTRACT FROM AUTHOR]
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- 2024
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14. Minimal Involvement of P-gp and BCRP in Oral Absorption of Ensitrelvir, An Oral SARS-CoV-2 3C-like Protease Inhibitor, in a Non-Clinical Investigation.
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Watari, Ryosuke, Tamura, Naomi, Yoshida, Shinpei, Kido, Yasuto, and Matsuzaki, Takanobu
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ORAL drug administration , *ATP-binding cassette transporters , *DRUG interactions , *BREAST cancer , *P-glycoprotein , *RATS , *MICE - Abstract
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are important transporters causing drug-drug interaction (DDI). Here, we investigated the involvement of P-gp and BCRP in the oral absorption of ensitrelvir in non-clinical studies and estimated the DDI risk mediated by P-gp and BCRP inhibition in humans. Although ensitrelvir is an in vitro P-gp and BCRP substrate, it demonstrated high bioavailability in rats and monkeys after oral administration. Plasma exposures of ensitrelvir following oral administration were comparable in wild type (WT) and Bcrp (-/-) mice. On the other hand, the area under the plasma concentration-time curve (AUC) ratio of ensitrelvir in the Mdr1a/1b (-/-) mice to the WT mice was 1.92, indicating that P-gp, but not BCRP, was involved in the oral absorption of ensitrelvir. Based on our previous retrospective analyses, such a low AUC ratio (<3) in the Mdr1a/1b (-/-) mice indicates a minimal impact of P-gp on the oral absorption in humans. In conclusion, our studies demonstrate that the involvement of both P-gp and BCRP in the oral absorption of ensitrelvir is minimal, and suggest that ensitrelvir has a low risk for DDIs mediated by P-gp and BCRP inhibition in humans. [Display omitted] [ABSTRACT FROM AUTHOR]
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- 2024
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15. ClonoScreen3D – A Novel 3-Dimensional Clonogenic Screening Platform for Identification of Radiosensitizers for Glioblastoma.
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Jackson, Mark R., Richards, Amanda R., Oladipupo, Abdul-Basit Ayoola, Chahal, Sandeep K., Caragher, Seamus, Chalmers, Anthony J., and Gomez-Roman, Natividad
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DNA repair , *MEDICAL screening , *DRUG interactions , *GLIOBLASTOMA multiforme , *SURVIVAL rate - Abstract
Glioblastoma (GBM) is a lethal brain tumor. Standard-of-care treatment comprising surgery, radiation, and chemotherapy results in median survival rates of 12 to 15 months. Molecular-targeted agents identified using conventional 2-dimensional (2D) in vitro models of GBM have failed to improve outcome in patients, rendering such models inadequate for therapeutic target identification. A previously developed 3D GBM in vitro model that recapitulates key GBM clinical features and responses to molecular therapies was investigated for utility for screening novel radiation-drug combinations using gold-standard clonogenic survival as readout. Patient-derived GBM cell lines were optimized for inclusion in a 96-well plate 3D clonogenic screening platform, ClonoScreen3D. Radiation responses of GBM cells in this system were highly reproducible and comparable to those observed in low-throughout 3D assays. The screen methodology provided quantification of candidate drug single agent activity (half maximal effective concentration or EC 50) and the interaction between drug and radiation (radiation interaction ratio). The poly(ADP-ribose) polymerase inhibitors talazoparib, rucaparib, and olaparib each showed a significant interaction with radiation by ClonoScreen3D and were subsequently confirmed as true radiosensitizers by full clonogenic assay. Screening a panel of DNA damage response inhibitors revealed the expected propensity of these compounds to interact significantly with radiation (13/15 compounds). A second screen assessed a panel of compounds targeting pathways identified by transcriptomic analysis and demonstrated single agent activity and a previously unreported interaction with radiation of dinaciclib and cytarabine (radiation interaction ratio 1.28 and 1.90, respectively). These compounds were validated as radiosensitizers in full clonogenic assays (sensitizer enhancement ratio 1.47 and 1.35, respectively). The ClonoScreen3D platform was demonstrated to be a robust method to screen for single agent and radiation-drug combination activity. Using gold-standard clonogenicity, this assay is a tool for identification of radiosensitizers. We anticipate this technology will accelerate identification of novel radiation-drug combinations with genuine translational value. [ABSTRACT FROM AUTHOR]
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- 2024
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16. Predictors of valproic acid steady-state serum levels in adult and pediatric psychiatric inpatients: a comparative analysis.
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Avrahami, Matan, Liwinski, Timur, Eckstein, Zafrir, Peskin, Miriam, Perlman, Polina, Sarlon, Jan, Lang, Undine E., Amital, Daniela, and Weizman, Abraham
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VALPROIC acid , *PEOPLE with mental illness , *MOOD stabilizers , *DRUG monitoring , *DRUG interactions - Abstract
Rationale: : Valproic acid (VPA) is commonly used as a second-line mood stabilizer or augmentative agent in severe mental illnesses. However, population pharmacokinetic studies specific to psychiatric populations are limited, and clinical predictors for the precision application of VPA remain undefined. Objectives: To identify steady-state serum VPA level predictors in pediatric/adolescent and adult psychiatric inpatients. Methods: We analyzed data from 634 patients and 1,068 steady-state therapeutic drug monitoring (TDM) data points recorded from 2015 to 2021. Steady-state VPA levels were obtained after tapering during each hospitalization episode. Electronic patient records were screened for routine clinical parameters and co-medication. Generalized additive mixed models were employed to identify independent predictors. Results: Most TDM episodes involved patients with psychotic disorders, including schizophrenia (29.2%) and schizoaffective disorder (17.3%). Polypharmacy was common, with the most frequent combinations being VPA + quetiapine and VPA + promethazine. Age was significantly associated with VPA levels, with pediatric/adolescent patients (< 18 years) demonstrating higher dose-adjusted serum levels of VPA (β = 7.6±2.34, p < 0.001) after accounting for BMI. Women tended to have higher adjusted VPA serum levels than men (β = 5.08±1.62, p < 0.001). The formulation of VPA (Immediate-release vs. extended-release) showed no association with VPA levels. Co-administration of diazepam exhibited a dose-dependent decrease in VPA levels (F = 15.7, p < 0.001), suggesting a potential pharmacokinetic interaction. Conclusions: This study highlights the utility of population-specific pharmacokinetic data for VPA in psychiatric populations. Age, gender, and co-administration of diazepam were identified as predictors of VPA levels. Further research is warranted to establish additional predictors and optimize the precision application of VPA in psychiatric patients. [ABSTRACT FROM AUTHOR]
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- 2024
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17. A substructure‐aware graph neural network incorporating relation features for drug–drug interaction prediction.
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Dong, Liangcheng, Feng, Baoming, Deng, Zengqian, Wang, Jinlong, Ni, Peihao, and Zhang, Yuanyuan
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GRAPH neural networks , *DRUG interactions , *DIRECTED graphs , *DATA mining , *DRUG design , *DRUG development - Abstract
Identifying drug–drug interactions (DDIs) is an important aspect of drug design research, and predicting DDIs serves as a crucial guarantee for avoiding potential adverse effects. Current substructure‐based prediction methods still have some limitations: (i) The process of substructure extraction does not fully exploit the graph structure information of drugs, as it only evaluates the importance of different radius substructures from a single perspective. (ii) The process of constructing drug representations has overlooked the significant impact of relation embedding on optimizing drug representations. In this work, we propose a substructure‐aware graph neural network incorporating relation features (RFSA‐DDI) for DDI prediction, which introduces a directed message passing neural network with substructure attention mechanism based on graph self‐adaptive pooling (GSP‐DMPNN) and a substructure‐aware interaction module incorporating relation features (RSAM). GSP‐DMPNN utilizes graph self‐adaptive pooling to comprehensively consider node features and local drug information for adaptive extraction of substructures. RSAM interacts drug features with relation representations to enhance their respective features individually, highlighting substructures that significantly impact predictions. RFSA‐DDI is evaluated on two real‐world datasets. Compared to existing methods, RFSA‐DDI demonstrates certain advantages in both transductive and inductive settings, effectively handling the task of predicting DDIs for unseen drugs and exhibiting good generalization capability. The experimental results show that RFSA‐DDI can effectively capture valuable structural information of drugs more accurately for DDI prediction, and provide more reliable assistance for potential DDIs detection in drug development and treatment stages. [ABSTRACT FROM AUTHOR]
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- 2024
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18. HIV and kidney transplantation in Romania: The index case.
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Sorohan, Bogdan Marian, Ismail, Gener, Oprea, Cristiana, Tacu, Dorina, Constantinescu, Ileana, Domnișor, Liliana, Manea, Ionuț, Sinescu, Ioanel, and Baston, Cătălin
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REVERSE transcriptase inhibitors ,NUCLEOSIDE reverse transcriptase inhibitors ,HIV ,CHRONIC kidney failure ,DRUG interactions - Abstract
Human immunodeficiency virus (HIV) is no longer considered a contraindication for kidney transplantation (KT). KT management in HIV patients is a complex process with challenges, such as drug interactions between immunosuppression and antiretroviral (ARV) therapy. In our country, no KT has been performed thus far in this category of patients. We present the case of a 29-year-old female patient with HIV and end-stage renal disease (ESRD) who performed a KT from a related living donor in March 2022. KT immediate evolution was favorable. No transplant-related complications were reported. HIV viral load remained undetectable and CD4+ T cells were constantly > 500 cell/ μL, during the 18 months of follow-up. The main challenge in our case was the drug interaction between the protease inhibitor-based regimen and tacrolimus. This led to tacrolimus overdose, and, subsequently, change in ARV therapy. ARV switching was performed on a regimen based on integrase inhibitor and nucleoside reverse transcriptase inhibitors. After the ARV change, the therapeutic level of tacrolimus was easily reached and maintained. Kidney graft function remained normal during follow-up, despite tacrolimus overexposure, and no rejection or anti-HLA antibodies were observed. Another challenge was related to the donor's hepatitis C virus status (positive antibodies, negative nucleic acid test). The recipient did not develop seroconversion or detectable viremia at 3-, 6-, 12- and 18-months post-KT. We reported the first case of a successful KT in an ESRD patient with HIV in Romania, in whom the post-transplant evolution was favorable. [ABSTRACT FROM AUTHOR]
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- 2024
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19. Pharmakotherapie und Polymedikation beim geriatrischen Patienten.
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Dartsch, Dorothee C. and Volkenstein, Reinhard
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Copyright of Die MKG-Chirurgie is the property of Springer Nature 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.)
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- 2024
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20. Influence of carbonyl cyanide m-chlorophenyl hydrazone on biofilm dynamics, protease, and siderophore production by Burkholderia pseudomallei.
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Guedes, Glaucia Morgana de Melo, Ocadaque, Crister José, Amando, Bruno Rocha, Freitas, Alyne Soares, Pereira, Vinicius Carvalho, Cordeiro, Rossana de Aguiar, Bandeira, Silviane Praciano, Souza, Pedro Filho Noronha, Rocha, Marcos Fábio Gadelha, Sidrim, José Júlio Costa, and Souza Collares Maia Castelo-Branco, Débora de
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BURKHOLDERIA pseudomallei ,DRUG interactions ,BIOFILMS ,FACTORS of production ,DRUG resistance in microorganisms - Abstract
Efflux pump inhibitors are a potential therapeutic strategy for managing antimicrobial resistance and biofilm formation. This article evaluated the effect of carbonyl cyanide m-chlorophenyl hydrazone (CCCP) on the biofilm growth dynamics and the production of virulence factors by Burkholderia pseudomallei. The effects of CCCP on planktonic, growing, and mature biofilm, interaction with antibacterial drugs, and protease and siderophore production were assessed. CCCP MICs ranged between 128 and 256 µM. The CCCP (128 µM) had a synergic effect with all the antibiotics tested against biofilms. Additionally, CCCP reduced (p <.05) the biomass of biofilm growth and mature biofilms at 128 and 512 µM, respectively. CCCP also decreased (p <.05) protease production by growing (128 µM) and induced (p <.05) siderophore release by planktonic cells (128 µM) growing biofilms (12.8 and 128 µM) and mature biofilms (512 µM). CCCP demonstrates potential as a therapeutic adjuvant for disassembling B. pseudomallei biofilms and enhancing drug penetration. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Management of patients with heart failure and chronic kidney disease.
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Wu, Lingling, Rodriguez, Mario, Hachem, Karim El, Tang, W. H. Wilson, and Krittanawong, Chayakrit
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CHRONIC kidney failure ,HEART failure patients ,MEDICAL care ,DRUG interactions ,KIDNEY physiology ,HEART failure - Abstract
Chronic kidney disease (CKD) and heart failure are often co-existing conditions due to a shared pathophysiological process involving neurohormonal activation and hemodynamic maladaptation. A wide range of pharmaceutical and interventional tools are available to patients with CKD, consisting of traditional ones with decades of experience and newer emerging therapies that are rapidly reshaping the landscape of medical care for this population. Management of patients with heart failure and CKD requires a stepwise approach based on renal function and the clinical phenotype of heart failure. This is often challenging due to altered drug pharmacokinetics interactions with various degrees of kidney function and frequent adverse effects from the therapy that lead to poor patient tolerance. Despite a great body of clinical evidence and guidelines that have offered various treatment options for patients with heart failure and CKD, respectively, patients with CKD are still underrepresented in heart failure clinical trials, especially for those with advanced CKD and end-stage renal disease (ESRD). Future studies are needed to better understand the generalizability of these therapeutic options among heart failures with different stages of CKD. [ABSTRACT FROM AUTHOR]
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- 2024
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22. Pharmacokinetics and Safety of Cilofexor and Firsocostat in Healthy Japanese and Non‐Japanese Participants.
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Younis, Islam R., Nelson, Cara, Weber, Elijah J., Shen, Gong, Qin, Ann R., Xiao, Deqing, Watkins, Timothy R., and Othman, Ahmed A.
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NON-alcoholic fatty liver disease , *CLINICAL pharmacology , *DRUG interactions , *DRUG administration , *PHARMACOKINETICS - Abstract
Cilofexor, an oral farnesoid X receptor agonist, and firsocostat, an oral, liver‐targeted inhibitor of acetyl‐coenzyme A carboxylase, are being investigated in combination with semaglutide for the treatment of metabolic dysfunction‐associated steatohepatitis (previously known as nonalcoholic steatohepatitis; NCT04971785). The pharmacokinetics and safety profiles of cilofexor (100 mg) and firsocostat (20 mg) were separately investigated in two phase 1 studies, each of which included healthy Japanese participants (n = 20 in the cilofexor study and n = 21 in the firsocostat study) and non‐Japanese participants (n = 20 in the cilofexor study and n = 21 in the firsocostat study). Intensive pharmacokinetic sampling was performed over 96 h following a single‐dose administration of the study drug. Safety was monitored throughout the study. In total, 39 participants completed each study. The plasma exposures of cilofexor and firsocostat (area under the concentration–time curve [AUC] calculated from time 0 to infinity [AUCinf]) in Japanese participants were 1.24‐fold and 1.98‐fold, respectively, of those in non‐Japanese participants. Both study drugs were well tolerated with no clear differences in adverse events or laboratory abnormalities between Japanese and non‐Japanese participants. The approximate 2‐fold exposure difference of firsocostat between Japanese and non‐Japanese participants at the 20 mg dose does not warrant dose reduction given the previously established safety and tolerability of once‐daily doses of firsocostat up to 200 mg. [ABSTRACT FROM AUTHOR]
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- 2024
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23. Development and validation of a reversed-phase HPLC-UV method for simultaneous determination of levosulpiride and omeprazole in human plasma: Applicability of the method for evaluation of pharmacokinetic drug-drug interactions.
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Hashim, Muhammad, Ahmad, Lateef, Khan, Amjad, and Faheem, Muhammad
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DRUG interactions , *ETHYL acetate , *DETECTION limit , *ACETONITRILE , *PHARMACOKINETICS , *OMEPRAZOLE - Abstract
Levosulpiride and omeprazole are co-prescribed for gastrointestinal disorders associated with depression and anxiety. Objective of the study was to develop a sensitive, robust and simple method for simultaneous analysis of levosulpiride and omeprazole in human plasma and applicability of the method in determination of pharmacokinetics drug-drug interaction. In the presented study, a reversed-phase HPLC-UV method was developed for the simultaneous determination of levosulpiride and omeprazole using pantoprazole as the internal standard. Experimental conditions were optimized and the developed method was validated as per standard guidelines (USP and ICH). Furthermore, the developed method was applied for evaluation of pharmacokinetics drug-drug interaction between levosulpiride (50 mg) and omeprazole (40 mg) in healthy human volunteers. Sharpsil C8 column (4.6 × 250 mm, 5 μm), Ultisil C8 column (4.6 mm × 150 mm, 5 μm) and Agilent C18 column (4.6 × 250 mm, 5 μm) were evaluated as stationary phase. The best resolution was achieved with Agilent C18 (4.6 x 250 mm, 5 μm) column and was selected for further study. The mobile phase consisted of a mixture of acetonitrile and phosphate buffer (pH 7.2) in 60:40 by volume, and was pumped at a flow rate of 1 mL/min. Detector wavelength was set at 280 nm. Levosulpiride and omeprazole were extracted from human plasma with ethyl acetate and dichloromethane (4:1, v/v). The calibration curves for both levosulpiride (5–150 ng/mL) and omeprazole (10–1500 ng/mL) were linear. The lower limit of quantification and limit of detection for levosulpiride were 5 and 2 ng/mL, while for omeprazole these were 10 and 3 ng/mL, respectively. Pharmacokinetics analysis showed that co-administration of omeprazole increased the AUC and Cmax of levosulpiride, while the clearance was reduced. Both the changes were insignificant. Similarly, no significant change in the pharmacokinetic parameters of omeprazole was observed with co-administration of levosulpiride. [ABSTRACT FROM AUTHOR]
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- 2024
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24. Physiologically based pharmacokinetic models for predicting lamotrigine exposure and dose optimization in pediatric patients receiving combination therapy with carbamazepine or valproic acid.
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Liu, Zhiwei, Shao, Wenxin, Wang, Xingwen, Geng, Kuo, Wang, Wenhui, Li, Yiming, Chen, Youjun, and Xie, Haitang
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VALPROIC acid , *PRESCHOOL children , *CHILD patients , *DRUG interactions , *ANTICONVULSANTS - Abstract
Introduction Method Results Conclusion Lamotrigine (LTG) is an antiepileptic drug that has been used in pediatric epilepsy as a combination therapy or monotherapy after stabilization in recent years. However, there are significant drug–drug interactions (DDI) between LTG and combined drugs such as carbamazepine (CBZ) and valproic acid (VPA). It is particularly important to consider the risk of DDI in combination therapy for intractable epilepsy in pediatric patients. Therefore, it is necessary to adjust the dosage of LTG accordingly. The aim of this study was to establish and validate a pediatric physiologically based pharmacokinetic (PBPK) model for predicting LTG exposure. The model is designed to explore the potential for quantifying pharmacokinetic (PK) DDI of LTG when administered concurrently with CBZ or VPA in pediatric patients.Adult and pediatric PBPK models for LTG and VPA were developed using PK‐Sim® software in combination with physiological information and drug‐specific parameters, and a DDI model was developed in combination with the published CBZ model. The models were validated against available PK data.Predictive and observational results in adults, children, and the DDI model were in good agreement. The recommended doses of LTG for preschool children (2–6 years) and school‐aged children (6–12 years) in the absence of drug interactions were 1.47 and 1.2 times higher than those for adults, respectively; 3.1 and 2.6 times higher than those for adults in combination with CBZ; and 0.67 and 0.57 times lower than those for adults in combination with VPA. In addition, plasma exposures in adolescents (12–18 years) were similar to those in adults at the same doses.We have successfully developed PBPK models and DDI models for LTG in adults and children, which provide a reference for rational drug use in the pediatric population. [ABSTRACT FROM AUTHOR]
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- 2024
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25. Mechanism-based inactivation of cytochromes P450: implications in drug interactions and pharmacotherapy.
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Tan, Boon Hooi, Ahemad, Nafees, Pan, Yan, and Ong, Chin Eng
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ENZYME metabolism , *DRUG toxicity , *CYTOTOXINS , *DRUG therapy , *PHARMACOKINETICS , *XENOBIOTICS , *DRUG interactions - Abstract
AbstractCytochrome P40 (CYP) enzymes dominate the metabolism of numerous endogenous and xenobiotic substances. While it is commonly believed that CYP-catalysed reactions result in the detoxication of foreign substances, these reactions can also yield reactive intermediates that can bind to cellular macromolecules to cause cytotoxicity or irreversibly inactivate CYPs that create them.Mechanism-based inactivation (MBI) produces either irreversible or quasi-irreversible inactivation and is commonly caused by CYP metabolic bioactivation to an electrophilic reactive intermediate. Many drugs that have been known to cause MBI in CYPs have been discovered as perpetrators in drug-drug interactions throughout the last 20–30 years.This review will highlight the key findings from the recent literature about the mechanisms of CYP enzyme inhibition, with a focus on the broad mechanistic elements of MBI for widely used drugs linked to the phenomenon. There will also be a brief discussion of the clinical or pharmacokinetic consequences of CYP inactivation with regard to drug interaction and toxicity risk.Gaining knowledge about the selective inactivation of CYPs by common therapeutic drugs helps with the assessment of factors that affect the systemic clearance of co-administered drugs and improves comprehension of anticipated interactions with other drugs or xenobiotics.Cytochrome P40 (CYP) enzymes dominate the metabolism of numerous endogenous and xenobiotic substances. While it is commonly believed that CYP-catalysed reactions result in the detoxication of foreign substances, these reactions can also yield reactive intermediates that can bind to cellular macromolecules to cause cytotoxicity or irreversibly inactivate CYPs that create them.Mechanism-based inactivation (MBI) produces either irreversible or quasi-irreversible inactivation and is commonly caused by CYP metabolic bioactivation to an electrophilic reactive intermediate. Many drugs that have been known to cause MBI in CYPs have been discovered as perpetrators in drug-drug interactions throughout the last 20–30 years.This review will highlight the key findings from the recent literature about the mechanisms of CYP enzyme inhibition, with a focus on the broad mechanistic elements of MBI for widely used drugs linked to the phenomenon. There will also be a brief discussion of the clinical or pharmacokinetic consequences of CYP inactivation with regard to drug interaction and toxicity risk.Gaining knowledge about the selective inactivation of CYPs by common therapeutic drugs helps with the assessment of factors that affect the systemic clearance of co-administered drugs and improves comprehension of anticipated interactions with other drugs or xenobiotics. [ABSTRACT FROM AUTHOR]
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- 2024
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26. Evaluation of Novel Hydrazone‐Imide Hybrid Compound as HNE Inhibitor In Silico: Synthesis, XRD and DFT Analysis.
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Eryilmaz, Serpil, Gul, Melek, and Ozek Yildirim, Arzu
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HYDRAZONE derivatives , *X-ray diffraction , *LEUCOCYTE elastase , *MOLECULAR docking , *BINDING energy , *DRUG interactions - Abstract
Investigation into the interactions between drugs and biomolecules can offer a precise understanding of their biological behaviours in vitro and in vivo, providing crucial insights for designing new drugs. Herein, we report the design, synthesis, and characterization of a bicyclic hydrazone derivative, along with its potential as an inhibitor of human neutrophil elastase (HNE), a critical enzyme in the treatment of acute and chronic lung injuries. We present an improved protocol for the synthesis of the compound using N‐amino‐bicyclo[2.2.1]hept‐5‐ene‐2,endo‐3‐endo‐dicarboximide and 4‐(trifluoromethyl)benzaldehyde through a facile, one‐pot, catalyst‐free synthesis in dry ethanol at reflux temperature. Within 12 hours, bicyclic‐hydrazone derivative was obtained with yields of up to 75 % and was characterized using various spectroscopic techniques and computational analyses based on the DFT approach. In silico ADME/T profile of the compound was evaluated and molecular docking simulation was utilized to predict its potential as a HNE inhibitor. The binding energy values of the THI ligand to the chosen PDB ID: 5ABW, 3Q77, and 2RG3 target proteins were determined as −8.41, −7.20, and −7.27 kcal/mol, respectively. In silico analysis findings indicate that the THI compound has promising drug‐likeness properties and has the potential to be evaluated in the development of new HNE inhibitors. [ABSTRACT FROM AUTHOR]
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- 2024
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27. Unveiling potential drug targets for lung squamous cell carcinoma through the integration of druggable genome and genome-wide association data.
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Wenhua Wu, Zhengrui Chen, Haiteng Wen, and Haiyun Zhang
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GENOME-wide association studies ,SQUAMOUS cell carcinoma ,DRUG target ,DRUG development ,DRUG interactions - Abstract
Background: Lung squamous cell carcinoma (LSCC) is a major subtype of lung cancer with poor prognosis and low survival rate. Compared with lung adenocarcinoma, yet no FDA-approved targeted-therapy has been found for lung squamous cell carcinoma. Methods: To identify potential drug targets for LSCC, Summary-data-based Mendelian randomization (SMR) analysis was used to examine the potential association between 4,543 druggable genes and LSCC, followed by colocalization analysis and HEIDI tests to confirm the robustness of the result. Phenome-wide association study (PheWAS) explored potential side effects of candidate drug targets. Enrichment analysis and protein-protein interaction networks revealed the function and significance of therapeutic targets. Singlecell expression analysis was used to examine cell types with enrichment expression of druggable genes in LSCC tissue. Drug prediction included screening potential drug candidates and evaluating their interactions with targets through molecular docking. Results: This research has identified ten significant drug targets for LSCC through a comprehensive SMR analysis. These targets included (COPA, PKD2L1, CCR1, C2, CYP21A2, and NCSTN as risk factors, and CCNA2, C4A, APOM, and LPAR2 as protective factors). PheWAS demonstrated that C2, CCNA2, LPAR2, and NCSTN exhibited associations with other phenotypes at the genetic level. Then, we found four potentially effective drugs with the Dsigdb database. Subsequently, molecular docking indicated that favorable binding interactions between drug candidates and potential target molecules. In the druggability evaluation, five out of ten drug target genes have been used in drug development (APOM, C4A, CCNA2, COPA, and PKD2L1). Six out of ten druggable genes showed significant expression in LSCC tissues (COPA, PKD2L1, CCR1, C2, NCSTN, LPAR2). Besides, Single-cell expression analysis revealed that C2 and CCNA2 were primarily enriched in macrophages, while COPA and NCSTN were enriched in both macrophages and epithelial cells. Conclusion: Our research revealed ten potential druggable genes for LSCC treatment, which might help to advance the precise and efficient therapeutic approaches of LSCC. [ABSTRACT FROM AUTHOR]
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- 2024
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28. Insights into pharmacogenetics, drug-gene interactions, and drug-drug-gene interactions.
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Russell, Laura E., Claw, Katrina G., Aagaard, Kaja M., Glass, Sarah M., Dasgupta, Kuheli, Nez, F. Leah, Haimbaugh, Alex, Maldonato, Benjamin J., and Yadav, Jaydeep
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DRUG side effects , *GENETIC variation , *GENETIC models , *GENE expression , *DRUG interactions - Abstract
AbstractThis review explores genetic contributors to drug interactions, known as drug-gene and drug-drug-gene interactions (DGI and DDGI, respectively). This article is part of a mini-review issue led by the International Society for the Study of Xenobiotics (ISSX) New Investigators Group. Pharmacogenetics (PGx) is the study of the impact of genetic variation on pharmacokinetics (PK), pharmacodynamics (PD), and adverse drug reactions. Genetic variation in pharmacogenes, including drug metabolizing enzymes and drug transporters, is common and can increase the risk of adverse drug events or contribute to reduced efficacy. In this review, we summarize clinically actionable genetic variants, and touch on methodologies such as genotyping patient DNA to identify genetic variation in targeted genes, and deep mutational scanning as a high-throughput
in vitro approach to study the impact of genetic variation on protein function and/or expressionin vitro . We highlight the utility of physiologically based pharmacokinetic (PBPK) models to integrate genetic and chemical inhibitor and inducer data for more accurate human PK simulations. Additionally, we analyze the limitations of historical ethnic descriptors in pharmacogenomics research. Altogether, the work herein underscores the importance of identifying and understanding complex DGI and DDGIs with the intention to provide better treatment outcomes for patients. We also highlight current barriers to wide-scale implementation of PGx-guided dosing as standard or care in clinical settings. [ABSTRACT FROM AUTHOR]- Published
- 2024
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29. The impact of thermophysical properties on eflornithine drug solute in acetone and ethyl acetate solvent interactions at varying concentrations and temperatures.
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Tegegn, Dereje Fedasa and Wirtu, Shuma Fayera
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MOLECULAR volume , *ETHYL acetate , *POLAR solvents , *DRUG interactions , *EMPIRICAL research , *THERMOPHYSICAL properties , *ACETONE - Abstract
The study was conducted on the impact of thermophysical properties on eflornithine drug solute–solvent interactions in aqueous ethyl acetate and acetone at different concentrations and temperatures. The aim of this study is to enhance the understanding of eflornithine's behavior in different solvents, which is crucial for its effective use in pharmaceutical applications. The density, molar volume, viscometric, and conductometric characteristics of the eflornithine drug solutions (0.025, 0.05, 0.075, 0.1, and 0.125 mol/kg) in acetone and 25% (v/v) aqueous ethyl acetate were measured within a temperature range of 298.15 K–318.15 K. Based on the determined density parameters, the following parameters were assessed: viscosity (η), equivalent molar conductance, limiting apparent molar volume (V0φ), apparent molar volume of transfer (V0φtr), and apparent molar volume (Vφ). The Masson empirical relationship and the viscosity-to-Jones-Dole (JD) equation were used to evaluate the partial molar volume (Vφ), experimental slope (SV), viscosity, and density data. Temperature and concentration were used to determine each parameter. For each set of dilutions, conductometric studies were conducted in both study solvents. The gathered data was analyzed in order to evaluate the ion–solvent interactions. The Walden product Λomηo's positive temperature coefficient values indicate that the drug eflornithine functions as a structural modifier in acetone and aqueous acetyl acetate systems. The structure-making and breaking characteristics of the polar solvents acetone and ethyl acetate were identified. [ABSTRACT FROM AUTHOR]
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- 2024
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30. A Bayesian method to detect drug‐drug interaction using external information for spontaneous reporting system.
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Tada, Keisuke, Maruo, Kazushi, and Gosho, Masahiko
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DRUG interactions , *DRUG side effects , *CLINICAL drug trials , *DATABASES - Abstract
Due to the insufficiency of safety assessments of clinical trials for drugs, further assessments are required for post‐marketed drugs. In addition to adverse drug reactions (ADRs) induced by one drug, drug‐drug interaction (DDI)‐induced ADR should also be investigated. The spontaneous reporting system (SRS) is a powerful tool for evaluating the safety of drugs continually. In this study, we propose a novel Bayesian method for detecting potential DDIs in a database collected by the SRS. By applying a power prior, the proposed method can borrow information from similar drugs for a drug assessed DDI to increase sensitivity of detection. The proposed method can also adjust the amount of the information borrowed by tuning the parameters in power prior. In the simulation study, we demonstrate the aforementioned increase in sensitivity. Depending on the scenarios, approximately 20 points of sensitivity of the proposed method increase from an existing method to a maximum. We also indicate the possibility of early detection of potential DDIs by the proposed method through analysis of the database shared by the Food and Drug Administration. In conclusion, the proposed method has a higher sensitivity and a novel criterion to detect potential DDIs early, provided similar drugs have similar observed‐expected ratios to the drug under assessment. [ABSTRACT FROM AUTHOR]
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- 2024
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31. Tracing the Evolution: A Comprehensive Bibliometric Analysis of Drug Interaction Clinical Studies.
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Li, Lanping, Zhou, Yushi, Ye, Lika, and Xie, Zhihong
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BIBLIOMETRICS , *DRUG metabolism , *DRUG interactions , *MEDICAL research , *THERAPEUTICS - Abstract
This study aims to meticulously map the bibliometric landscape of drug‐drug interactions (DDIs) in clinical research. This represents the first use of bibliometric analysis to comprehensively highlight the evolutionary trends and core themes in this critical field of pharmacology. An exhaustive bibliometric search was performed within the Web of Science Core Collection, aiming to comprehensively gather literature on DDIs in clinical settings. A combination of sophisticated analytical tools including DIKW, VOSviewer, and Citespace was utilized for an in‐depth exploration of bibliometric patterns and trends. Of the 3421 initially identified articles, 2622 were considered relevant. The analysis revealed a marked escalation in DDIs publications, with a peak observed in 2020. Five principal thematic clusters emerged: Safety and Adverse Reactions, Drug Metabolism and Efficacy, Disease and Drug Treatment, Research Methods and Practices, and Special Populations and Combined Medication. Key insights included the escalating significance of drug metabolism in pharmacokinetics, heightened focus on cardiovascular and antiviral therapeutics, and the advancing frontier of personalized medicine. Additionally, the analysis underscored the necessity for strategic attention to vulnerable populations and innovative methodological approaches. This study calls for the global harmonization of research methods in DDIs clinical investigations, advocating for the integration of personalized medicine paradigms and the implementation of cutting‐edge computational analytics. It highlights the imperative for inclusive and collaborative research approaches to adeptly address the intricate challenges of contemporary pharmacotherapy. [ABSTRACT FROM AUTHOR]
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- 2024
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32. CAVIN1-Mediated hERG Dynamics: A Novel Mechanism Underlying the Interindividual Variability in Drug-Induced Long QT.
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Al Sayed, Zeina R., Pereira, Céline, Le Borgne, Rémi, de Lesegno, Christine Viaris, Jouve, Charlène, Pénard, Esthel, Mallet, Adeline, Masurkar, Nihar, Loussouarn, Gildas, Verbavatz, Jean-Marc, Lamaze, Christophe, Trégouët, David-Alexandre, and Hulot, Jean-Sébastien
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DRUG side effects , *SMALL interfering RNA , *PLURIPOTENT stem cells , *LONG QT syndrome , *DRUG interactions - Abstract
BACKGROUND: Drug-induced QT prolongation (diLQT) is a feared side effect that could expose susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily attributed to unintended drug interactions with cardiac ion channels, notably the hERG (human ether-a-go-go-related gene) channels that generate the delayed-rectifier potassium current (IKr) and thereby regulate the late repolarization phase. There is an important interindividual susceptibility to develop diLQT, which is of unknown origin but can be reproduced in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs). We aimed to investigate the dynamics of hERG channels in response to sotalol and to identify regulators of the susceptibility to developing diLQT. METHODS: We measured electrophysiological activity and cellular distribution of hERG channels after hERG blocker treatment in iPS-CMs derived from patients with highest sensitivity (HS) or lowest sensitivity (LS) to sotalol administration in vivo (ie, on the basis of the measure of the maximal change in QT interval 3 hours after administration). Specific small interfering RNAs and CAVIN1-T2A-GFP adenovirus were used to manipulate CAVIN1 expression. RESULTS: Whereas HS and LS iPS-CMs showed similar electrophysiological characteristics at baseline, the late repolarization phase was prolonged and IKr significantly decreased after exposure of HS iPS-CMs to low sotalol concentrations. IKr reduction was caused by a rapid translocation of hERG channel from the membrane to the cytoskeleton-associated fractions upon sotalol application. CAVIN1, essential for caveolae biogenesis, was 2× more highly expressed in HS iPS-CMs, and its knockdown by small interfering RNA reduced their sensitivity to sotalol. CAVIN1 overexpression in LS iPS-CMs using adenovirus showed reciprocal effects. We found that treatment with sotalol promoted translocation of the hERG channel from the plasma membrane to the cytoskeleton fractions in a process dependent on CAVIN1 (caveolae associated protein 1) expression. CAVIN1 silencing reduced the number of caveolae at the membrane and abrogated the translocation of hERG channel in sotalol-treated HS iPS-CMs. CAVIN1 also controlled cardiomyocyte responses to other hERG blockers, such as E4031, vandetanib, and clarithromycin. CONCLUSIONS: Our study identifies unbridled turnover of the potassium channel hERG as a mechanism supporting the interindividual susceptibility underlying diLQT development and demonstrates how this phenomenon is finely tuned by CAVIN1. [ABSTRACT FROM AUTHOR]
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- 2024
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33. Binding studies of promethazine and its metabolites with human serum albumin by high-performance affinity chromatography and molecular docking in the presence of codeine.
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Coelho, Maria Miguel, Lima, Rita, Almeida, Ana Sofia, Fernandes, Pedro Alexandrino, Remião, Fernando, Fernandes, Carla, and Tiritan, Maria Elizabeth
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AFFINITY chromatography , *BLOOD proteins , *MOLECULAR docking , *DRUG interactions , *PROMETHAZINE - Abstract
"Purple Drank", a soft drink containing promethazine (PMZ) and codeine (COD), has gained global popularity for its hallucinogenic effects. Consuming large amounts of this combination can lead to potentially fatal events. The binding of these drugs to plasma proteins can exacerbate the issue by increasing the risk of drug interactions, side effects, and/or toxicity. Herein, the binding affinity to human serum albumin (HSA) of PMZ and its primary metabolites [N-desmethyl promethazine (DMPMZ) and promethazine sulphoxide (PMZSO)], along with COD, was investigated by high-performance affinity chromatography (HPAC) though zonal approach. PMZ and its metabolites exhibited a notable binding affinity for HSA (%b values higher than 80%), while COD exhibited a %b value of 65%. To discern the specific sites of HSA to which these compounds were bound, displacement experiments were performed using warfarin and (S)-ibuprofen as probes for sites I and II, respectively, which revealed that all analytes were bound to both sites. Molecular docking studies corroborated the experimental results, reinforcing the insights gained from the empirical data. The in silico data also suggested that competition between PMZ and its metabolites with COD can occur in both sites of HSA, but mainly in site II. As the target compounds are chiral, the enantioselectivity for HSA binding was also explored, showing that the binding for these compounds was not enantioselective. [ABSTRACT FROM AUTHOR]
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- 2024
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34. Salvianolic acid B in fibrosis treatment: a comprehensive review.
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Qingzhi Liang, Xiaoqin Liu, Xi Peng, Ting Luo, Yi Su, Xin Xu, Hongyan Xie, Hong Gao, Zhengtao Chen, and Chunguang Xie
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DRUG interactions ,PUBLIC health ,NATURAL products ,DRUG therapy ,EXTRACELLULAR matrix - Abstract
Fibrosis is a public health issue of great concern characterized by the excessive deposition of extracellular matrix, leading to the destruction of parenchymal tissue and organ dysfunction that places a heavy burden on the global healthcare system due to its high incidence, disability, and mortality. Salvianolic acid B (SalB) has positively affected various human diseases, including fibrosis. In this review, we concentrate on the anti-fibrotic effects of SalB from a molecular perspective while providing information on the safety, adverse effects, and drug interactions of SalB. Additionally, we discuss the innovative SalB formulations, which give some references for further investigation and therapeutic use of SalB's antifibrotic qualities. Even with the encouraging preclinical data, additional research is required before relevant clinical trials can be conducted. Therefore, we conclude with recommendations for future studies. It is hoped that this review will provide comprehensive new perspectives on future research and product development related to SalB treatment of fibrosis and promote the efficient development of this field. [ABSTRACT FROM AUTHOR]
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- 2024
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35. Using QSAR to predict polymer-drug interactions for drug delivery.
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Xin, Alison W., Rivera-Delgado, Edgardo, and von Recum, Horst A.
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CYCLODEXTRINS ,SMALL molecules ,ORDINARY differential equations ,DRUG interactions ,STRUCTURE-activity relationships - Abstract
Affinity-mediated drug delivery utilizes electrostatic, hydrophobic, or other noncovalent interactions between molecules and a polymer to extend the timeframe of drug release. Cyclodextrin polymers exhibit affinity interaction, however, experimentally testing drug candidates for affinity is time-consuming, making computational predictions more effective. One option, docking programs, provide predictions of affinity, but lack reliability, as their accuracy with cyclodextrin remains unverified experimentally. Alternatively, quantitative structure-activity relationship models (QSARs), which analyze statistical relationships between molecular properties, appear more promising. Previously constructed QSARs for cyclodextrin are not publicly available, necessitating an openly accessible model. Around 600 experimental affinities between cyclodextrin and guest molecules were cleaned and imported from published research. The software PaDEL-Descriptor calculated over 1,000 chemical descriptors for each molecule, which were then analyzed with R to create several QSARs with different statistical methods. These QSARs proved highly time efficient, calculating in minutes what docking programs could accomplish in hours. Additionally, on test sets, QSARs reached R2 values of around 0.7--0.8. The speed, accuracy, and accessibility of these QSARs improve evaluation of individual drugs and facilitate screening of large datasets for potential candidates in cyclodextrin affinity-based delivery systems. An app was built to rapidly access model predictions for end users using the Shiny library. To demonstrate the usability for drug release planning, the QSAR predictions were coupled with a mechanistic model of diffusion within the app. Integrating new modules should provide an accessible approach to use other cheminformatic tools in the field of drug delivery. [ABSTRACT FROM AUTHOR]
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- 2024
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36. The metabolic activation of and platelet response to vicagrel vary with P-glycoprotein deficiency, rather than P-glycoprotein inhibition, in mice.
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Li, Xue-Mei, Li, Hao-Dong, Shao, Yuan-Yuan, Ji, Jin-Zi, Tang, Ke, Zheng, Zhao-Dong, Wu, Yu, Ding, Pei-Jie, Wang, Jin, Jiang, Li-Ping, Tai, Ting, Mi, Qiong-Yu, Fu, Min, and Xie, Hong-Guang
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BIOTRANSFORMATION (Metabolism) , *BLOOD platelet aggregation , *BLOOD platelet activation , *DRUG interactions , *PROTEIN expression - Abstract
AbstractThis study aimed to determine changes in the hydrolysis of vicagrel, a substrate drug of arylacetamide deacetylase (Aadac) and carboxylesterase 2 (Ces2), in P-glycoprotein (P-gp)-deficient or P-gp-inhibited mice and to elucidate the mechanisms involved.Male wild-type (WT) and P-gp knock-out (KO) mice were used to investigate the systemic exposure of vicagrel thiol active metabolite H4 and platelet response to vicagrel, and the mRNA and protein expression levels of intestinal Aadac and Ces2. Moreover, WT mice were administered vicagrel alone or in combination with elacridar (a potent P-gp inhibitor) to determine drug-drug interactions.Compared with WT mice, P-gp KO mice exhibited significant increases in the systemic exposure of H4, the protein expression levels of intestinal Aadac and Ces2, and inhibition of ADP-induced platelet aggregation by vicagrel. Further, the H4 exposure was positively correlated with intestinal Aadac protein expression levels but did not vary with short-term inhibition of P-gp efflux activity by elacridar.P-gp-deficient mice, rather than elacridar-treated mice, exhibited significant upregulation of intestinal Aadac and Ces2 and thus, enhanced metabolic activation of and platelet response to vicagrel, suggesting that the metabolic activation of vicagrel may vary with P-gp deficiency, not P-gp inhibition, in mice.This study aimed to determine changes in the hydrolysis of vicagrel, a substrate drug of arylacetamide deacetylase (Aadac) and carboxylesterase 2 (Ces2), in P-glycoprotein (P-gp)-deficient or P-gp-inhibited mice and to elucidate the mechanisms involved.Male wild-type (WT) and P-gp knock-out (KO) mice were used to investigate the systemic exposure of vicagrel thiol active metabolite H4 and platelet response to vicagrel, and the mRNA and protein expression levels of intestinal Aadac and Ces2. Moreover, WT mice were administered vicagrel alone or in combination with elacridar (a potent P-gp inhibitor) to determine drug-drug interactions.Compared with WT mice, P-gp KO mice exhibited significant increases in the systemic exposure of H4, the protein expression levels of intestinal Aadac and Ces2, and inhibition of ADP-induced platelet aggregation by vicagrel. Further, the H4 exposure was positively correlated with intestinal Aadac protein expression levels but did not vary with short-term inhibition of P-gp efflux activity by elacridar.P-gp-deficient mice, rather than elacridar-treated mice, exhibited significant upregulation of intestinal Aadac and Ces2 and thus, enhanced metabolic activation of and platelet response to vicagrel, suggesting that the metabolic activation of vicagrel may vary with P-gp deficiency, not P-gp inhibition, in mice. [ABSTRACT FROM AUTHOR]
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- 2024
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37. Muscular toxicity of colchicine combined with statins: a real-world study based on the FDA adverse event reporting system database from 2004-2023.
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Ying Liu, Chunyan Wei, Yanling Yuan, Dan Zou, and Bin Wu
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DATABASES ,DRUG interactions ,FOOD chemistry ,COLCHICINE ,PITAVASTATIN - Abstract
Background: Through an analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS), we explored the signal strength of adverse reactions (ADRs) related to myopathy caused by the combination of colchicine and statins and gained insight into the characteristics of these myopathy related ADRs. Methods: We extracted data from the FAERS database about ADRs in individuals with myopathy resulting from the combination of colchicine and statins. The analysis was conducted for the period spanning from January 2004 to December 2023 using the reported odds ratio (ROR) and information component (IC) methods to assess muscle-related ADR signals. Results: A total of 18,386 reports of statin myopathy-associated adverse reactions, 348 colchicine myopathy-associated adverse reactions, and 461 muscle-associated adverse reactions due to the combination of the two were collected; the strongest signals of statin myotoxicity events were for necrotizing myositis (ROR 50.47, 95% CL 41.74-61.01; IC 3.70 95% CL 3.25-4.08); the strongest signal for colchicine myotoxicity events was toxic myopathy (ROR 32.50, 95% CL 19.74-53.51; IC 4.97 95% CL 1.89-5.10), and the strongest signal for statins combined with colchicine was toxic myopathy (ROR 159.85, 95% CL 111.60-228.98; IC 7.22 95% CL 3.59-5.9); muscle-related adverse reactions signals were meaningful when the two drugs were combined in the order of colchicine combined with fluvastatin (ROR 187.38, 95% CL 96.68-363.17; IC 6.99 95% CL 1.65-5.68); colchicine combined with simvastatin in 135 cases (ROR 30.08. 95% CL 25.25-35.85; IC 4.80 95% CL 3.96-5.12); and colchicine combined with rosuvastatin (ROR 25.73, 95% CL 20.16-32.83; IC 4.59 95% CL 3.38-4.98) versus colchicine combined with atorvastatin (ROR 25.73, 95% CL 22.33-29.66; IC 4.59 95% CL 3.97-4.91) with almost identical signal intensity, followed by colchicine combined with pravastatin (ROR 13.67, 95% CL 9.17-20.37; IC 3.73 95% CL 1.87-4.47), whereas no signals were generated for lovastatin or pitavastatin. Conclusion: Similar ADRs can occur when colchicine and statins are used individually or in combination; however, the strength of these reactions may differ. To minimize the risk of drug interactions, statins with less potential interactions, such as lovastatin, pitavastatin, and pravastatin, should be chosen, and myopathy-related indices and symptoms should be closely monitored during use. [ABSTRACT FROM AUTHOR]
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- 2024
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38. A cross-sectional study on metoprolol concentrations in various biological samples and their inter-correlations.
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Houshyar, Jalil, Hashemzadeh, Nastaran, Khoubnasabjafari, Maryam, Sarmadian, Amirreza Jabbaripour, Jouyban-Gharamaleki, Vahid, Mogaddam, Mohammad Reza Afshar, Khosrowshahi, Elnaz Marzi, and Jouyban, Abolghasem
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DRUG monitoring ,METOPROLOL ,DRUG interactions ,INDIVIDUALIZED medicine ,LIQUID chromatography - Abstract
Background: Concentrations of metoprolol in exhaled breath condensate (EBC) have not been investigated. Herein, we aim to determine the metoprolol levels in EBC, plasma, and urine samples. Methods: Biological samples were collected from 39 patients receiving metoprolol. Metoprolol was determined using liquid chromatography mass spectrometery. The obtained metoprolol levels in biological fluids were investigated for possible inter-correlations. Results: Acceptable linearity was obtained with coefficient of determinations equal to 0.9998, 0.9941, and 0.9963 for EBC, plasma, and urine samples, respectively. The calibration curves were linear in the ranges of 0.6–500, 0.4–500, and 0.7–10,000 µg·L
− 1 regarding EBC, plasma, and urine samples, respectively. The detection and quantification limits were (0.18, 0.12, and 0.21 µg·L− 1 ) and (0.60, 0.40, and 0.70 µg·L− 1 ) for EBC, plasma, and urine samples, respectively. The relative standard deviations for the intra- and inter-day replications were obtained between 5.2 and 6.1 and 3.3–4.6%, respectively. The obtained mean metoprolol levels in EBC, plasma, and urine samples of 39 patients were 5.35, 70.76, and 1943.1 µg·L− 1 . There were correlations between daily dose and plasma and urinary concentrations of metoprolol in the investigated samples, whereas no significant correlation was observed for daily dose and EBC levels. The correlation among plasma-urine levels was significant, however, the non-significant correlation was obtained between plasma and EBC concentrations. Conclusion: Metoprolol levels varied widely due to the metabolic pattern of the Azeri population, different dosages received by the patients, formulation effects, age, sex, and interactions with the co-administered drugs. A poor correlation of EBC-plasma concentrations and a significant correlation of plasma-urine concentrations were observed. Further investigations are required to provide the updated services to personalized medicine departments. [ABSTRACT FROM AUTHOR]- Published
- 2024
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39. In vitro and in vivo preclinical pharmacokinetic characterization of aficamten, a small molecule cardiac myosin inhibitor.
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Sukhun, Rajaa, Cremin, Peadar, Xu, Donghong, Zamora, Jeanelle, Cheung, Jennifer, Ashcraft, Luke, Grillo, Mark P., and Morgan, Bradley P.
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LIVER microsomes , *SMALL molecules , *DRUG interactions , *CELL permeability , *MONKEYS - Abstract
AbstractAficamten, a small molecule selective inhibitor of cardiac myosin, was characterised in preclinical
in vitro andin vivo studies.Protein binding in human plasma was 10.4% unbound and ranged from 1.6% to 24.9% unbound across species. Blood-to-plasma ratios ranged from 0.69 to 1.14 across species. Aficamten hepatic clearance in human was predicted to be low from observed high metabolic stabilityin vitro in human liver microsomes. Aficamten demonstrated high permeability in Caco-2 cell monolayers.Aficamtenin vivo clearance was low across species at 8.8, 2.1, 3.3, and 11 mL/min/kg in mouse, rat, dog, and monkey, respectively. The volume of distribution was low-to-high ranging from 0.53 in rat to 11 L/kg in dog. Oral bioavailability ranged from 41% in monkey to 98% in mouse.Aficamten was metabolisedin vitro to eight metabolites with hydroxylated metabolites M1a and M1b predominating. CYP phenotyping indicated multiple CYPs (2C8, 2C9, 2D6, and 3A4) contributing to the metabolism of aficamten.Human clearance (1.1 mL/min/kg) and volume of distribution (6.5 L/kg) were predicted using 4-species allometry employing ‘rule-of-exponents’. A predicted 69 hour half-life is consistent with observed half-life in human Phase-1.No CYP-based drug-drug interaction liability as a precipitant was predicted for aficamten.Aficamten, a small molecule selective inhibitor of cardiac myosin, was characterised in preclinicalin vitro andin vivo studies.Protein binding in human plasma was 10.4% unbound and ranged from 1.6% to 24.9% unbound across species. Blood-to-plasma ratios ranged from 0.69 to 1.14 across species. Aficamten hepatic clearance in human was predicted to be low from observed high metabolic stabilityin vitro in human liver microsomes. Aficamten demonstrated high permeability in Caco-2 cell monolayers.Aficamtenin vivo clearance was low across species at 8.8, 2.1, 3.3, and 11 mL/min/kg in mouse, rat, dog, and monkey, respectively. The volume of distribution was low-to-high ranging from 0.53 in rat to 11 L/kg in dog. Oral bioavailability ranged from 41% in monkey to 98% in mouse.Aficamten was metabolisedin vitro to eight metabolites with hydroxylated metabolites M1a and M1b predominating. CYP phenotyping indicated multiple CYPs (2C8, 2C9, 2D6, and 3A4) contributing to the metabolism of aficamten.Human clearance (1.1 mL/min/kg) and volume of distribution (6.5 L/kg) were predicted using 4-species allometry employing ‘rule-of-exponents’. A predicted 69 hour half-life is consistent with observed half-life in human Phase-1.No CYP-based drug-drug interaction liability as a precipitant was predicted for aficamten. [ABSTRACT FROM AUTHOR]- Published
- 2024
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40. Characteristics of CYP3A4-related potential drug-drug interactions in outpatients receiving prescriptions from multiple clinical departments.
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Matsuoka, Rina, Akagi, Shinsuke, Konishi, Tomohiro, Kondo, Masashi, Matsubara, Hideki, Yamamoto, Shohei, Izushi, Keiji, and Tasaka, Yuichi
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DRUG side effects ,MULTIPLE regression analysis ,DRUG interactions ,DRUG monitoring ,CARDIOVASCULAR agents - Abstract
Background: Drug-drug interactions (DDIs) increase the incidence of adverse drug reactions (ADRs). In a previous report, we revealed that the incidence of potential DDIs due to the same CYP molecular species in one prescription exceeds 90% among patients taking six or more drugs and that CYP3A4 markedly influences the increase in the number of potential DDIs in clinical practice. However, the factors contributing to an increased number of potential DDIs in prescriptions from multiple clinical departments remain poorly clarified. Methods: This observational study was performed at five pharmacies in Okayama Prefecture, Japan. Patients who visited these pharmacies from 11 April 2022 to 24 April 2022 were included, except those who had prescriptions only from a single clinical department. A stratified analysis was performed to determine the incidence of CYP3A4-related potential DDIs according to the number of drugs taken. Additionally, factors associated with an increase in the number of drugs involved in CYP3A4-related potential DDIs were identified using multiple linear regression analysis. In this study, potential DDIs for the prescription data subdivided by clinical department, containing two or more drugs, were used as control data. Results: Overall, 372 outpatients who received prescriptions from multiple clinical departments were included in the current study. The number of drugs contributing to CYP3A4-related potential DDIs increased with an increase in the number of clinical departments. Notably, in cases taking fewer than six drugs, prescriptions from multiple clinical departments had a higher frequency of CYP3A4-related potential DDIs than those in prescriptions subdivided by clinical department. Multiple regression analysis identified "Cardiovascular agents", "Agents affecting central nervous system", and "Urogenital and anal organ agents" as the top three drug classes that increase CYP3A4-related potential DDIs. Conclusion: Collectively, these results highlight the importance of a unified management strategy for prescribed drugs and continuous monitoring of ADRs in outpatients receiving prescriptions from multiple clinical departments even if the number of drugs taken is less than six. [ABSTRACT FROM AUTHOR]
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- 2024
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41. 肺动脉高压的抗凝治疗:必要性与困境.
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胡崧, 华潞, and 张健
- Abstract
Pulmonary hypertension (PH) is a rare and life-threatening disease. Over past two decades, rapid advancements in treatment techniques have significantly improved the prognosis of two major subgroups of PH entities: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Given the underlying pathological feature of in situ thrombosis of small arteries, anti-coagulation was previously considered to be a supportive therapy for PAH to improve prognosis. However, due to a lack of robust evidence, it is not recommended by the current guidelines. In contrast, lifelong anticoagulation is recommended for CTEPH patients to prevent thrombus recurrence and in situ thrombosis, based on the thromboembolic etiology. Furthermore, with the advent of direct oral anticoagulants, there are now more options for anti-coagulation therapy in PH. Nevertheless, due to the complexity of PH etiology and the heterogeneity of treatment approaches, anti-coagulation management remains challenging. This article reviews and evaluates the current status and safety issue of anti-coagulation therapy for PH patients, providing guidance and insights for clinical practice and research in this field. [ABSTRACT FROM AUTHOR]
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- 2024
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42. A newly developed algorithm for switching outpatient medications to medications listed in the hospital formulary: a prospective real-word evaluation in patients admitted electively to hospital.
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Möller, Finja, Oetting, Malte, Spiegel, Andreas, Zube, Olaf, and Bertsche, Thilo
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MEDICAL prescriptions , *HOSPITAL care , *MEDICATION reconciliation , *DESCRIPTIVE statistics , *MEDICATION error prevention , *PATIENT care , *LONGITUDINAL method , *DRUG interactions , *GENERIC drug substitution , *ALGORITHMS - Abstract
Purpose: In many countries, outpatient and inpatient care are separated. During hospitalization, therefore, switching the outpatient medication to medication of the hospital formulary is required. Methods: We newly designed a switching algorithm in six switching steps (S0–S5) and conducted a study at Bundeswehr Hospital Hamburg (300 beds, 80% civilians). We performed (i) a medication reconciliation to obtain information on outpatient medications and (ii) a medication review to solve drug-related-problems, e.g., drug-drug interactions. We applied (iii) the algorithm to switch medications to the hospital formulary. Results: (i) We identified 475 outpatient medications (median per patient: 4; Q25/Q75 2/7) in 100 patients consecutively admitted to hospital (median age: 71; Q25/Q75: 64/80 years). Of 475 medications, the switching algorithm could not be used since product names were missing in 23.9% and strength in 1.7%. In 3.2%, switching was not required since medication was not prescribed during the hospital stay. (ii) Drug-drug interactions were identified in 31 of 79 patients with more than one medication. (iii) Of 475 medications, 18.5% were on the hospital formulary and therefore did not need to be switched (S0), 0.2% were on a substitution-exclusion list not allowing switching (S1), 42.0% were switched to a generic medication of the hospital formulary (S2), 1.7% to a therapeutically equivalent medication (S3), 0.4% were patient-individually switched (S4), and for 8.2% a standardized/patient-individual switching was not possible (S5). Conclusions: Despite comprehensive medication reconciliation, patient- and medication-related information for switching medications to the hospital formulary was often missing. Once all the necessary information was available, standardized switching could be easily carried out according to a newly developed switching algorithm. [ABSTRACT FROM AUTHOR]
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- 2024
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43. Pharmacokinetics of nirmatrelvir/ritonavir and the drug-drug interaction with calcineurin inhibitor in renal transplant recipients.
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Xu, Xueyin, Zhang, Huanxi, Liu, Longshan, Fu, Qian, Wu, Chenglin, Lin, Xiaobin, Tang, Kejing, Wang, Changxi, and Chen, Pan
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KIDNEY physiology , *KIDNEY transplantation , *HIGH performance liquid chromatography , *PATIENTS , *TRANSPLANTATION of organs, tissues, etc. , *LIQUID chromatography-mass spectrometry , *ERYTHROCYTES , *DATA analysis , *RECEIVER operating characteristic curves , *CREATININE , *RESEARCH funding , *ENZYME inhibitors , *HEMOGLOBINS , *TERMINATION of treatment , *IN vivo studies , *PROTEASE inhibitors , *LONGITUDINAL method , *DRUG interactions , *STATISTICS , *HEMATOCRIT , *TACROLIMUS , *RITONAVIR , *GENOTYPES - Abstract
Objectives: To describe the pharmacokinetic (PK) characteristics of nirmatrelvir/ritonavir in renal transplant recipients and explore the potential factors that related to the PK variance of nirmatrelvir/ritonavir and its interaction with calcineurin inhibitor (CNI). Methods: Renal transplant recipients treated with CNI and nirmatrelvir/ritonavir were prospectively enrolled. Steady-state plasma concentrations of nirmatrelvir/ritonavir were determined by high-performance liquid chromatography-tandem mass spectrometry, and the PK parameters were calculated using non-compartmental analysis. Spearman correlation analysis was used for exploring influencing factors. Results: A total of eight recipients were enrolled; for nirmatrelvir and ritonavir, AUC/dose was 0.24179 ± 0.14495 and 0.06196 ± 0.03767 μg·h·mL-1·mg-1. Red blood cell (RBC), hematocrit (Ht), hemoglobins (Hb), and creatinine clearance (Ccr) were negatively correlated with AUC/dose of nirmatrelvir, while Ccr, CYP3A5 genotype, and CYP3A4 genotype were related to the AUC/dose of ritonavir. Ccr was negatively correlated with the C0/dose of tacrolimus (TAC) after termination of nirmatrelvir/ritonavir (rs = -0.943, p = 0.008). Conclusions: The PK characteristics of nirmatrelvir/ritonavir vary greatly among renal transplant recipients. Factors including Ccr and CYP3A5 genotype were related to the in vivo exposure of nirmatrelvir/ritonavir. During the whole process before and after nirmatrelvir/ritonavir therapy, it is recommended to adjust the CNI basing on renal function to avoid CNI toxicity exposure. [ABSTRACT FROM AUTHOR]
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- 2024
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44. Effect of propranolol on pharmacokinetics of clozapine in schizophrenic patients: a meta-analysis.
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Yang, Xiding, Yan, Qiangyong, Yang, Lingfeng, Li, Jingjing, Fan, Xiao, Chen, Jindong, Wu, Haishan, Yang, Yongyu, Zhu, Ronghua, and Fang, Pingfei
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PROPRANOLOL , *RESEARCH funding , *TREATMENT effectiveness , *META-analysis , *DECISION making in clinical medicine , *DRUG interactions , *PHYSICIAN practice patterns , *TACHYCARDIA , *HEALTH facilities , *DATA analysis software , *CONFIDENCE intervals , *BIOAVAILABILITY , *DRUG prescribing , *CLOZAPINE , *PHARMACODYNAMICS , *EVALUATION ,DRUG therapy for schizophrenia - Abstract
Purpose: Clozapine is the effective therapy for treatment-refractory schizophrenia. However, the use of clozapine is limited by its adverse effects. As propranolol is frequently used for the prevention and treatment of clozapine-induced tachycardia, we performed a meta-analysis to evaluate the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients. Methods: We included 16 retrospective studies on the effects of propranolol on steady state pharmacokinetics of clozapine in schizophrenic patients, with data from both generic and brand name treatment phases in eight clozapine bioequivalence studies conducted in a single center in China from 2018 to 2022. Review Manager 5.4 was used for meta-analysis of the included studies. Results: The SMDs with 95% CIs of AUC0–12, Cmax,ss, C, and C were calculated to be 0.44 (0.23, 0.64), 0.40 (0.20, 0.61), 0.43 (0.22, 0.63), and 0.44 (0.23, 0.64), respectively. These findings proved that combination with propranolol would increase the systemic exposure of clozapine. T1/2 of clozapine was significantly longer in the presence of propranolol than in the absence of propranolol (SMD = 0.32, 95% CI [0.12, 0.52], p = 0.002). There was no statistically significant difference for T of clozapine in the presence or absence of propranolol (SMD = − 0.05, 95% CI [− 0.25, 0.15], p = 0.63). Conclusion: The combination with propranolol could significantly increase systemic exposure and extended T1/2 of clozapine, and thus need to be considered in prescribing decisions. [ABSTRACT FROM AUTHOR]
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- 2024
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45. Anti‐Helicobacter pylori Infection Treatment and Pulmonary Hypersensitivity: Case Series and Review of the Literature.
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Xu, Shan, Wu, Xiaohong, Chen, Enguo, and Ying, Kejing
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INTERSTITIAL lung diseases , *LITERATURE reviews , *DRUG interactions , *HELICOBACTER pylori , *LUNG diseases , *HELICOBACTER pylori infections - Abstract
Background: Helicobacter pylori (H. pylori) infection is currently widespread throughout the world. Bismuth‐containing quadruple therapy is widely used, but it has rarely been associated with interstitial lung disease. Case Presentation: We described six cases with similar clinical symptoms and typical pulmonary interstitial imaging changes during anti‐H. pylori therapy, usually on Days 7–12 following treatment. Anti‐H. pylori infection treatment was discontinued when it was suspected to be the cause of the clinical symptoms, and all of the patients accepted observation therapy. All of them had a favorable outcome, the clinical symptoms returned to normal almost 1 week later, and the chest computed tomography (CT) scan images showed remarkable absorption 4 weeks later. Conclusions: Drug interactions could be the cause, and the most likely drug was furazolidone. All of the patients recovered quickly after drug discontinuation, and low‐dose steroid may help shorten the recovery time. [ABSTRACT FROM AUTHOR]
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- 2024
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46. Assessment of CYP‐Mediated Drug Interactions for Enasidenib Based on a Cocktail Study in Patients with Relapse or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome.
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Cheng, Yiming, Wang, Xiaomin, Ghosh, Atalanta, Pu, Jie, Carayannopoulos, Leonidas N, and Li, Yan
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MYELODYSPLASTIC syndromes , *MEMBRANE transport proteins , *PIOGLITAZONE , *IN vitro studies , *CANCER relapse , *RESEARCH funding , *ANTINEOPLASTIC agents , *DEXTROMETHORPHAN , *CANCER patients , *FLURBIPROFEN , *DESCRIPTIVE statistics , *TREATMENT effectiveness , *DRUG interactions , *CYTOCHROME P-450 , *CONFIDENCE intervals , *COMPARATIVE studies , *PHARMACODYNAMICS - Abstract
As a selective and potent inhibitor targeting the isocitrate dehydrogenase‐2 (IDH2) mutant protein, enasidenib obtained approval from the US Food and Drug Administration (FDA) in 2017 for adult patients with acute myeloid leukemia (AML) with an IDH2 mutation. In vitro investigations demonstrated that enasidenib affects various drug metabolic enzymes and transporters. This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug), omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. Results showed that following the co‐administration of enasidenib (100 mg, once daily) for 28 days, the PK parameters AUC(0‐∞) and Cmax of dextromethorphan increased by 1.37 (90% confidence interval (CI): 0.96, 1.96) and 1.24 (90% CI: 0.94, 1.65)‐fold, respectively, compared to dextromethorphan alone. For flurbiprofen, these parameters increased by 1.14 (90%CI: 1.01, 1.29) and 0.97 (90% CI 0.86, 1.08)‐fold, respectively, when compared to flurbiprofen alone. Conversely, midazolam exhibited decreases to 0.57 (90% CI 0.34, 0.97) and 0.77 (90% CI 0.39, 1.53)‐fold, respectively, in comparison to midazolam alone. The parameters for omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)‐fold, respectively, compared to omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)‐fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib. [ABSTRACT FROM AUTHOR]
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- 2024
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47. Qualitative and quantitative status of cytochrome P450s after the administration of a liposomal platelet substitute in rat liver.
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Taguchi, Kazuaki, Hashimoto, Mai, Tokuno, Masahiro, Takeoka, Shinji, Maruyama, Toru, Yamasaki, Keishi, and Otagiri, Masaki
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WESTERN immunoblotting , *DRUG interactions , *BLOOD substitutes , *CYTOCHROME P-450 , *GENE expression - Abstract
AbstractIn the process of the drug development, studies on the cytochrome P450 (CYP) profiles after its administration provided fundamental information regarding drug interactions with concomitantly administered drugs. Here, we evaluated the influence of the administration of H12-(ADP)-liposomes, a platelet substitute, on the mRNA and protein expression, and metabolic activity of CYPs, with focus on the CYP1A2, CYP2C11 and CYP3A2, in rat liver.At 24 h after administering saline or H12-(ADP)-liposomes (10 mg of lipids/kg), a quantitative RT-PCR and western blot analysis revealed that the mRNA and proteins expression of all of the target hepatic CYP isoforms were not different between the saline and H12-(ADP)-liposome groups. Furthermore, an
ex vivo CYP metabolic activity assay showed that hepatic CYP metabolic activities in the H12-(ADP)-liposome group were comparable to the corresponding saline group. On the other hand, the area under the blood concentration-time curve for substitutes for CYP1A2 and CYP2C11 was higher in H12-(ADP)-liposome group than in saline group, but the degree of elevations was negligible levels.At a minimum, based on these results, we conclude that H12-(ADP)-liposomes have no quantitative and qualitative effect on the hepatic CYP isoforms, indicating that the drug interactions of H12-(ADP)-liposomes with CYP-metabolizing drugs would be negligible.In the process of the drug development, studies on the cytochrome P450 (CYP) profiles after its administration provided fundamental information regarding drug interactions with concomitantly administered drugs. Here, we evaluated the influence of the administration of H12-(ADP)-liposomes, a platelet substitute, on the mRNA and protein expression, and metabolic activity of CYPs, with focus on the CYP1A2, CYP2C11 and CYP3A2, in rat liver.At 24 h after administering saline or H12-(ADP)-liposomes (10 mg of lipids/kg), a quantitative RT-PCR and western blot analysis revealed that the mRNA and proteins expression of all of the target hepatic CYP isoforms were not different between the saline and H12-(ADP)-liposome groups. Furthermore, anex vivo CYP metabolic activity assay showed that hepatic CYP metabolic activities in the H12-(ADP)-liposome group were comparable to the corresponding saline group. On the other hand, the area under the blood concentration-time curve for substitutes for CYP1A2 and CYP2C11 was higher in H12-(ADP)-liposome group than in saline group, but the degree of elevations was negligible levels.At a minimum, based on these results, we conclude that H12-(ADP)-liposomes have no quantitative and qualitative effect on the hepatic CYP isoforms, indicating that the drug interactions of H12-(ADP)-liposomes with CYP-metabolizing drugs would be negligible. [ABSTRACT FROM AUTHOR]- Published
- 2024
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48. 药物联合应用对中草药相关肝损伤的影响.
- Author
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郑 晖 and 孙 蓉
- Abstract
With the wide application of traditional Chinese medicine (TCM)globally and combined drug use in clinical practice, there have been significant increases in herb-induced liver injury (HILI) events and drug safety events, bringing great challenges to the research and development of new TCM drugs and the development of the TCM industry. At present, there are still shortcomings in systematically summarizing the effect of combined drug use on HILI and analyzing its clinical features, pathogenesis and interaction mechanism, especially the research on pharmacodynamics and pharmacotoxicology processes after the combination of TCM and Western drugs. It is urgently needed to further construct an integrated research system, especially in the aspects of target molecules, intercellular communication, tissue crosstalk, and in vivo toxicity assessment. Based on the basic research combining clinical and fundamental studies, it is necessary to put forward HILI prevention and control strategies in accordance with TCM theory and application rules, which will provide fundamental support and reliable evidence for improving the level of combined use of TCM and Western drugs in the context of diseases and syndromes. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
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49. Effect of Carbamazepine on the Pharmacokinetics of Erdafitinib in Healthy Participants.
- Author
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Jaiprasart, Pharavee, Hellemans, Peter, Jiao, Juhui James, Dosne, Anne‐Gaëlle, De Meulder, Marc, De Zwart, Loeckie, Brees, Laurane, and Zhu, Wei
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CARBAMAZEPINE , *DRUG interactions , *CYTOCHROME P-450 CYP3A , *ENZYMES , *ADULTS - Abstract
Erdafitinib, a selective and potent oral pan‐FGFR inhibitor, is metabolized mainly through CYP2C9 and CYP3A4 enzymes. This phase 1, open‐label, single‐sequence, drug‐drug interaction study evaluated the pharmacokinetics, safety, and tolerability of a single oral dose of erdafitinib alone and when co‐administered with steady state oral carbamazepine, a dual inducer of CYP3A4 and CYP2C9, in 13 healthy adult participants (NCT04330248). Compared with erdafitinib administration alone, carbamazepine co‐administration decreased total and free maximum plasma concentrations of erdafitinib (Cmax) by 35% (95% CI 30%‐39%) and 22% (95% CI 17%‐27%), respectively. The areas under the concentration‐time curve over the time interval from 0 to 168 hours, to the last quantifiable data point, and to time infinity (AUC168h, AUClast, AUCinf), were markedly decreased for both total erdafitinib (56%‐62%) and free erdafitinib (48%‐55%). The safety profile of erdafitinib was consistent with previous clinical studies in healthy participants, with no new safety concerns when administered with or without carbamazepine. Co‐administration with carbamazepine may reduce the activity of erdafitinib due to reduced exposure. Concomitant use of strong CYP3A4 inducers with erdafitinib should be avoided. [ABSTRACT FROM AUTHOR]
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- 2024
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50. Potentially Inappropriate Medications Involved in Drug–Drug Interactions in a Polish Population over 80 Years Old: An Observational, Cross-Sectional Study.
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Błeszyńska-Marunowska, Emilia, Jagiełło, Kacper, Wierucki, Łukasz, Renke, Marcin, Grodzicki, Tomasz, Kalarus, Zbigniew, and Zdrojewski, Tomasz
- Abstract
The clinical context of drug interactions detected by automated analysis systems is particularly important in older patients with multimorbidities. We aimed to provide unique, up-to-date data on the prevalence of potentially inappropriate medications (PIMs) and drug–drug interactions (DDIs) in the Polish geriatric population over 80 years old and determine the frequency and the most common PIMs involved in DDIs. We analyzed all non-prescription and prescription drugs in a representative national group of 178 home-dwelling adults over 80 years old with excessive polypharmacy (≥10 drugs). The FORTA List was used to assess PIMs, and the Lexicomp® Drug Interactions database was used for DDIs. DDIs were detected in 66.9% of the study group, whereas PIMs were detected in 94.4%. Verification of clinical indications for the use of substances involved in DDIs resulted in a reduction in the total number of DDIs by more than 1.5 times, as well as in a nearly 3-fold decrease in the number of interactions requiring therapy modification and drug combinations that should be strictly avoided. The most common PIMs involved in DDIs were painkillers, and drugs used in psychiatry and neurology. Special attention should be paid to DDIs with PIMs since they could increase their inappropriate character. The use of automated interaction analysis systems, while maintaining appropriate clinical criticism, can increase both chances for a good therapeutic effect and the safety of the elderly during treatment processes. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
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