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1.
Artigo em Inglês | MEDLINE | ID: mdl-39271639

RESUMO

BACKGROUND AND OBJECTIVES: Voriconazole administered concomitantly with flucloxacillin may result in subtherapeutic plasma concentrations as shown in a patient with Staphylococcus aureus sepsis and a probable pulmonary aspergillosis. After switching our patient to posaconazole, therapeutic concentrations were reached. The aim of this study was to first test our hypothesis that flucloxacillin competes with voriconazole not posaconazole for binding to albumin ex vivo, leading to lower total concentrations in plasma. METHODS: A physiologically based pharmacokinetic (PBPK) model was then applied to predict the mechanism of action of the drug-drug interaction (DDI). The model included non-linear hepatic metabolism and the effect of a severe infectious disease on cytochrome P450 (CYP) enzymes activity. RESULTS: The unbound voriconazole concentration remained unchanged in plasma after adding flucloxacillin, thereby rejecting our hypothesis of albumin-binding site competition. The PBPK model was able to adequately predict the plasma concentration of both voriconazole and posaconazole over time in healthy volunteers. Upregulation of CYP3A4, CYP2C9, and CYP2C19 through the pregnane X receptor (PXR) gene by flucloxacillin resulted in decreased voriconazole plasma concentrations, reflecting the DDI observations in our patient. Posaconazole metabolism was not affected, or was only limitedly affected, by the changes through the PXR gene, which agrees with the observed plasma concentrations within the target range in our patient. CONCLUSIONS: Ex vivo experiments reported that the unbound voriconazole plasma concentration remained unchanged after adding flucloxacillin. The PBPK model describes the potential mechanism driving the drug-drug and drug-disease interaction of voriconazole and flucloxacillin, highlighting the large substantial influence of flucloxacillin on the PXR gene and the influence of infection on voriconazole plasma concentrations, and suggests a more limited effect on other triazoles.

2.
Cancers (Basel) ; 15(5)2023 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-36900352

RESUMO

Glioblastoma multiforme is the most common primary central nervous system tumor, with an incidence of 3 [...].

3.
Eur J Pharm Sci ; 184: 106418, 2023 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-36870577

RESUMO

INTRODUCTION: In the randomized double-blind placebo-controlled CounterCOVID study, oral imatinib treatment conferred a positive clinical outcome and a signal for reduced mortality in COVID-19 patients. High concentrations of alpha-1 acid glycoprotein (AAG) were observed in these patients and were associated with increased total imatinib concentrations. AIMS: This post-hoc study aimed to compare the difference in exposure following oral imatinib administration in COVID-19 patients to cancer patients and assess assocations between pharmacokinetic (PK) parameters and pharmacodynamic (PD) outcomes of imatinib in COVID-19 patients. We hypothesize that a relatively higher drug exposure of imatinib in severe COVID-19 patients leads to improved pharmacodynamic outcome parameters. METHODS: 648 total concentration plasma samples obtained from 168 COVID-19 patients were compared to 475 samples of 105 cancer patients, using an AAG-binding model. Total trough concentration at steady state (Cttrough) and total average area under the concentration-time curve (AUCtave) were associated with ratio between partial oxygen pressure and fraction of inspired oxygen (P/F), WHO ordinal scale (WHO-score) and liberation of oxygen supplementation (O2lib). Linear regression, linear mixed effects models and time-to-event analysis were adjusted for possible confounders. RESULTS: AUCtave and Cttrough were respectively 2.21-fold (95%CI 2.07-2.37) and 1.53-fold (95%CI 1.44-1.63) lower for cancer compared to COVID-19 patients. Cttrough, not AUCtave, associated significantly with P/F (ß=-19,64; p-value=0.014) and O2lib (HR 0.78; p-value= 0.032), after adjusting for sex, age, neutrophil-lymphocyte ratio, dexamethasone concomitant treatment, AAG and baseline P/F-and WHO-score. Cttrough, but not AUCtave associated significantly with WHO-score. These results suggest an inverse relationship between PK-parameters, Cttrough and AUCtave, and PD outcomes. CONCLUSION: COVID-19 patients exhibit higher total imatinib exposure compared to cancer patients, attributed to differences in plasma protein concentrations. Higher imatinib exposure in COVID-19 patients did not associate with improved clinical outcomes. Cttrough and AUCtave inversely associated with some PD-outcomes, which may be biased by disease course, variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite may better explain exposure-response.


Assuntos
COVID-19 , Neoplasias , Humanos , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Reposicionamento de Medicamentos , Neoplasias/tratamento farmacológico
4.
CPT Pharmacometrics Syst Pharmacol ; 11(5): 640-652, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35213797

RESUMO

The use of systems-based pharmacological modeling approaches to characterize mode-of-action and concentration-effect relationships for drugs on specific hemodynamic variables has been demonstrated. Here, we (i) expand a previously developed hemodynamic system model through integration of cardiac output (CO) with contractility (CTR) using pressure-volume loop theory, and (ii) evaluate the contribution of CO data for identification of system-specific parameters, using atenolol as proof-of-concept drug. Previously collected experimental data was used to develop the systems model, and included measurements for heart rate (HR), CO, mean arterial pressure (MAP), and CTR after administration of atenolol (0.3-30 mg/kg) from three in vivo telemetry studies in conscious Beagle dogs. The developed cardiovascular (CVS)-contractility systems model adequately described the effect of atenolol on HR, CO, dP/dtmax, and MAP dynamics and allowed identification of both system- and drug-specific parameters with good precision. Model parameters were structurally identifiable, and the true mode of action can be identified properly. Omission of CO data did not lead to a significant change in parameter estimates compared to a model that included CO data. The newly developed CVS-contractility systems model characterizes short-term drug effects on CTR, CO, and other hemodynamic variables in an integrated and quantitative manner. When the baseline value of total peripheral resistance is predefined, CO data was not required to identify drug- and system-specific parameters. Confirmation of the consistency of system-specific parameters via inclusion of data for additional drugs and species is warranted. Ultimately, the developed model has the potential to be of relevance to support translational CVS safety studies.


Assuntos
Sistema Cardiovascular , Contração Miocárdica , Animais , Atenolol/farmacologia , Cães , Frequência Cardíaca , Hemodinâmica/fisiologia , Humanos , Contração Miocárdica/fisiologia
5.
Bioorg Med Chem ; 13(21): 5921-6, 2005 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-16154748

RESUMO

A novel series of cationic surfactants was prepared based on Mannich base (produced from the condensation of piperidine and/or morpholine as secondary amine and paraformaldehyde in the presence of 8-hydroxyquinoline). The chemical structures of the synthesized cationic surfactants were confirmed using elemental analyses, FTIR spectroscopy and 1H NMR. Surface activities of the prepared surfactants were measured including: surface tension (gamma), critical micelle concentration (CMC), effectiveness (pi(CMC)), efficiency (Pc20), maximum surface excess (Gamma(max)), minimum surface area (A(min)), interfacial tension (gamma(IT)), emulsification power and foaming power at 25 degrees C. The structural influences on their surface activities and adsorption free energy were discussed. The synthesized cationic surfactants were evaluated for their biocidal activity towards Gram +ve bacteria (Staph. Cocu., Bacillus), Gram -ve bacteria (Salmonella, E. coli), fungi (A. terrus., A. flav.) and yeast (Candida) at 1.0, 2.5 and 5.0mg/mL, respectively. The target compounds showed good inhibition towards Gram +ve bacteria, Gram -ve bacteria and yeast. Meanwhile, excellent fungicidal results were obtained against the various types of fungi under investigation.


Assuntos
Aminas/química , Aminas/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Adsorção , Aminas/síntese química , Antibacterianos/síntese química , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Cátions/química , Emulsões/química , Estrutura Molecular , Espectroscopia de Infravermelho com Transformada de Fourier , Tensão Superficial
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