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Heliyon Jun 2024It is difficult to differentiate between primary central nervous system lymphoma and primary glioblastoma due to their similar MRI findings. This study aimed to assess...
Differentiation between primary central nervous system lymphomas and gliomas according to pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging.
PURPOSE
It is difficult to differentiate between primary central nervous system lymphoma and primary glioblastoma due to their similar MRI findings. This study aimed to assess whether pharmacokinetic parameters derived from dynamic contrast-enhanced MRI could provide valuable insights for differentiation.
METHODS
Seventeen cases of primary central nervous system lymphoma and twenty-one cases of glioblastoma as confirmed by pathology, were retrospectively analyzed. Pharmacokinetic parameters, including K, K, V, and the initial area under the Gd concentration curve, were measured from the enhancing tumor parenchyma, peritumoral parenchyma, and contralateral normal parenchyma. Statistical comparisons were made using Mann-Whitney tests for V and Matrix Metallopeptidase-2, while independent samples -tests were used to compare pharmacokinetic parameters in the mentioned regions and pathological indicators of enhancing tumor parenchyma, such as vascular endothelial growth factor and microvessel density. The pharmacokinetic parameters with statistical differences were evaluated using receiver-operating characteristics analysis. Except for the Wilcoxon rank sum test for V, the pharmacokinetic parameters were compared within the enhancing tumor parenchyma, peritumoral parenchyma, and contralateral normal parenchyma of the primary central nervous system lymphomas and glioblastomas using variance analysis and the least-significant difference method.
RESULTS
Statistical differences were observed in K and K within the enhancing tumor parenchyma and in K within the peritumoral parenchyma between these two tumor types. Differences were also found in Matrix Metallopeptidase-2, vascular endothelial growth factor, and microvessel density within the enhancing tumor parenchyma of these tumors. When compared with the contralateral normal parenchyma, pharmacokinetic parameters within the peritumoral parenchyma and enhancing tumor parenchyma exhibited variations in glioblastoma and primary central nervous system lymphoma, respectively. Moreover, the receiver-operating characteristics analysis showed that the diagnostic efficiency of K in the peritumoral parenchyma was notably higher.
CONCLUSION
Pharmacokinetic parameters derived from dynamic contrast-enhanced MRI can differentiate primary central nervous system lymphoma and glioblastoma, especially K in the peritumoral parenchyma.
PubMed: 38952379
DOI: 10.1016/j.heliyon.2024.e32619 -
Veterinary Medicine and Science Jul 2024Although research on the mechanism and control of pain and inflammation in fish has increased in recent years, the use of analgesic drugs is limited due to the lack of...
BACKGROUND
Although research on the mechanism and control of pain and inflammation in fish has increased in recent years, the use of analgesic drugs is limited due to the lack of pharmacological information about analgesic drugs. Tolfenamic acid is a non-steroidal anti-inflammatory drug and can be used in fish due to its low side effect profile and superior pharmacokinetic properties.
OBJECTIVES
The pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid were investigated following single intravascular (IV), intramuscular (IM) and oral administration of 2 mg/kg in rainbow trout at 13 ± 0.5°C.
METHODS
The experiment was carried out on a total of 234 rainbow trout (Oncorhynchus mykiss). Tolfenamic acid was administered to fish via IV, IM and oral route at a dose of 2 mg/kg. Blood samples were taken at 13 different sampling times until the 72 h after drug administration. The plasma concentrations of tolfenamic acid were quantified using high pressure liquid chromatography-ultraviolet (UV) and pharmacokinetic parameters were assessed using non-compartmental analysis.
RESULTS
The elimination half-life (t) of tolfenamic acid for IV, IM and oral routes was 3.47, 6.75 and 9.19 h, respectively. For the IV route, the volume of distribution at a steady state and total body clearance of tolfenamic acid were 0.09 L/kg and 0.03 L/h/kg, respectively. The peak plasma concentration and bioavailability for IM and oral administration were 8.82 and 1.24 µg/mL, and 78.45% and 21.48%, respectively. The mean plasma protein binding ratio of tolfenamic acid in rainbow trout was 99.48% and was not concentration dependent.
CONCLUSIONS
While IM route, which exhibits both the high plasma concentration and bioavailability, can be used in rainbow trout, oral route is not recommended due to low plasma concentration and bioavailability. However, there is a need to demonstrate the pharmacodynamic activity of tolfenamic acid in rainbow trout.
Topics: Animals; Oncorhynchus mykiss; ortho-Aminobenzoates; Biological Availability; Anti-Inflammatory Agents, Non-Steroidal; Administration, Oral; Blood Proteins; Injections, Intramuscular; Protein Binding; Injections, Intravenous; Half-Life
PubMed: 38952278
DOI: 10.1002/vms3.1533 -
Clinical and Translational Science Jul 2024The AIDA randomized clinical trial found no significant difference in clinical failure or survival between colistin monotherapy and colistin-meropenem combination... (Randomized Controlled Trial)
Randomized Controlled Trial
The AIDA randomized clinical trial found no significant difference in clinical failure or survival between colistin monotherapy and colistin-meropenem combination therapy in carbapenem-resistant Gram-negative infections. The aim of this reverse translational study was to integrate all individual preclinical and clinical pharmacokinetic-pharmacodynamic (PKPD) data from the AIDA trial in a pharmacometric framework to explore whether individualized predictions of bacterial burden were associated with the trial outcomes. The compiled dataset included for each of the 207 patients was (i) information on the infecting Acinetobacter baumannii isolate (minimum inhibitory concentration, checkerboard assay data, and fitness in a murine model), (ii) colistin plasma concentrations and colistin and meropenem dosing history, and (iii) disease scores and demographics. The individual information was integrated into PKPD models, and the predicted change in bacterial count at 24 h for each patient, as well as patient characteristics, was correlated with clinical outcomes using logistic regression. The in vivo fitness was the most important factor for change in bacterial count. A model-predicted growth at 24 h of ≥2-log (164/207) correlated positively with clinical failure (adjusted odds ratio, aOR = 2.01). The aOR for one unit increase of other significant predictors were 1.24 for SOFA score, 1.19 for Charlson comorbidity index, and 1.01 for age. This study exemplifies how preclinical and clinical anti-infective PKPD data can be integrated through pharmacodynamic modeling and identify patient- and pathogen-specific factors related to clinical outcomes - an approach that may improve understanding of study outcomes.
Topics: Humans; Acinetobacter baumannii; Meropenem; Middle Aged; Microbial Sensitivity Tests; Female; Male; Anti-Bacterial Agents; Colistin; Adult; Aged; Animals; Treatment Outcome; Mice; Acinetobacter Infections; Translational Research, Biomedical; Drug Therapy, Combination; Models, Biological
PubMed: 38952168
DOI: 10.1111/cts.13870 -
Critical Reviews in Food Science and... Jul 2024The enterolignans, enterolactone and enterodiol, the main metabolites produced from plant lignans by the gut microbiota, have enhanced bioavailability and activity... (Review)
Review
The enterolignans, enterolactone and enterodiol, the main metabolites produced from plant lignans by the gut microbiota, have enhanced bioavailability and activity compared to their precursors, with beneficial effects on metabolic and cardiovascular health. Although extensively studied, the biosynthesis, cardiometabolic effects, and other therapeutic implications of mammalian lignans are still incompletely understood. The aim of this review is to provide a comprehensive overview of these phytoestrogen metabolites based on up-to-date information reported in studies from a wide range of disciplines. Established and novel synthetic strategies are described, as are the various lignan precursors, their dietary sources, and a proposed metabolic pathway for their conversion to enterolignans. The methodologies used for enterolignan analysis and the available data on pharmacokinetics and bioavailability are summarized and their cardiometabolic bioactivity is explored in detail. The special focus given to research on the health benefits of microbial-derived lignan metabolites underscores the critical role of lignan-rich diets in promoting cardiovascular health.
PubMed: 38952149
DOI: 10.1080/10408398.2024.2371939 -
Drug Delivery Dec 2024In this study, chitosan low molecular weight (LCH) and chitosan medium molecular weight (MCH) were employed to encapsulate a yarrow extract rich in chlorogenic acid and...
In this study, chitosan low molecular weight (LCH) and chitosan medium molecular weight (MCH) were employed to encapsulate a yarrow extract rich in chlorogenic acid and dicaffeoylquinic acids (DCQAs) that showed antiproliferative activity against colon adenocarcinoma cells. The design of CH micro/nanoparticles to increase the extract colon delivery was carried out by using two different techniques: ionic gelation and spray drying. Ionic gelation nanoparticles obtained were smaller and presented higher yields values than spray-drying microparticles, but spray-drying microparticles showed the best performance in terms of encapsulation efficiency (EE) (> 94%), also allowing the inclusion of a higher quantity of extract. Spray-drying microparticles designed using LCH with an LCH:extract ratio of 6:1 (1.25 mg/mL) showed a mean diameter of 1.31 ± 0.21 µm and EE values > 93%, for all phenolic compounds studied. The release profile of phenolic compounds included in this formulation, at gastrointestinal pHs (2 and 7.4), showed for most of them a small initial release, followed by an increase at 1 h, with a constant release up to 3 h. Chlorogenic acid presented the higher release values at 3 h (56.91% at pH 2; 44.45% at pH 7.4). DCQAs release at 3 h ranged between 9.01- 40.73%, being higher for 1,5- and 3,4-DCQAs. After gastrointestinal digestion, 67.65% of chlorogenic and most DCQAs remained encapsulated. Therefore, spray-drying microparticles can be proposed as a promising vehicle to increase the colon delivery of yarrow phenolics compounds (mainly chlorogenic acid and DCQAs) previously described as potential agents against colorectal cancer.
Topics: Chitosan; Humans; Plant Extracts; Achillea; Chlorogenic Acid; Nanoparticles; Cell Proliferation; Colorectal Neoplasms; Particle Size; Cell Line, Tumor; Quinic Acid; Drug Liberation; Drug Delivery Systems; Antineoplastic Agents, Phytogenic; Colon; Drug Carriers; Molecular Weight
PubMed: 38952133
DOI: 10.1080/10717544.2024.2372285 -
Drug Delivery Dec 2024Skin melanoma is considered the most dangerous form of skin cancer due to its association with high risk of metastasis, high mortality rate and high resistance to...
Skin melanoma is considered the most dangerous form of skin cancer due to its association with high risk of metastasis, high mortality rate and high resistance to different treatment options. Genistein is a natural isoflavonoid with known chemotherapeutic activity. Unfortunately, it has low bioavailability due to its poor aqueous solubility and excessive metabolism. In the current study, genistein was incorporated into transferosomal hydrogel to improve its bioavailability. The prepared transferosomal formulations were characterized regarding: particle size; polydispersity index; zeta potential; encapsulation efficiency; TEM; FTIR; DSC; XRD; drug release; viscosity; pH; anti-tumor activity on 3D skin melanoma spheroids and 1-year stability study at different storage temperatures. The optimized formulation has high encapsulation efficiency with an excellent particle size that will facilitate its penetration through the skin. The transfersomes have a spherical shape with sustained drug release profile. The anti-tumor activity evaluation of genistein transfersome revealed that genistein is a potent chemotherapeutic agent with enhanced penetration ability through the melanoma spheroids when incorporated into transfersomes. Stability study results demonstrate the high physical and chemical stability of our formulations. All these outcomes provide evidence that our genistein transferosomal hydrogel is a promising treatment option for skin melanoma.
Topics: Genistein; Melanoma; Skin Neoplasms; Humans; Particle Size; Drug Liberation; Hydrogels; Drug Delivery Systems; Cell Line, Tumor; Drug Stability; Antineoplastic Agents; Solubility; Drug Carriers; Chemistry, Pharmaceutical; Viscosity; Biological Availability; Administration, Cutaneous; Spheroids, Cellular
PubMed: 38952058
DOI: 10.1080/10717544.2024.2372277 -
Leukemia & Lymphoma Jul 2024This report focuses on part 3 of a multicenter, open-label, phase 1 study (NCT03198650) assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor...
This report focuses on part 3 of a multicenter, open-label, phase 1 study (NCT03198650) assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of acalabrutinib plus obinutuzumab in Japanese patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Ten patients were included; median age was 68 years. With a median treatment duration of 27.2 months, treatment-emergent adverse events (AEs) occurred in all patients (grade ≥3, 70%), and the most common AEs were anemia and headache (40% each). One patient had a grade 4 AE of neutropenia (the only dose-limiting toxicity). PK results suggested no marked effects of concomitant obinutuzumab treatment on the exposure of acalabrutinib. PD assessment indicated that combination therapy provided >98% Bruton tyrosine kinase (BTK) occupancy. Overall response rate (ORR) was 100% with median duration of response (DoR) and median progression-free survival (PFS) not reached. Treatment with acalabrutinib plus obinutuzumab was generally safe and efficacious in adult Japanese patients with TN CLL.
PubMed: 38952054
DOI: 10.1080/10428194.2024.2370436 -
Journal of Translational Medicine Jul 2024Triple-negative breast cancer (TNBC) is a recurrent, heterogeneous, and invasive form of breast cancer. The treatment of TNBC patients with paclitaxel and fluorouracil...
BACKGROUND
Triple-negative breast cancer (TNBC) is a recurrent, heterogeneous, and invasive form of breast cancer. The treatment of TNBC patients with paclitaxel and fluorouracil in a sequential manner has shown promising outcomes. However, it is challenging to deliver these chemotherapeutic agents sequentially to TNBC tumors. We aim to explore a precision therapy strategy for TNBC through the sequential delivery of paclitaxel and fluorouracil.
METHODS
We developed a dual chemo-loaded aptamer with redox-sensitive caged paclitaxel for rapid release and non-cleavable caged fluorouracil for slow release. The binding affinity to the target protein was validated using Enzyme-linked oligonucleotide assays and Surface plasmon resonance assays. The targeting and internalization abilities into tumors were confirmed using Flow cytometry assays and Confocal microscopy assays. The inhibitory effects on TNBC progression were evaluated by pharmacological studies in vitro and in vivo.
RESULTS
Various redox-responsive aptamer-paclitaxel conjugates were synthesized. Among them, AS1411-paclitaxel conjugate with a thioether linker (ASP) exhibited high anti-proliferation ability against TNBC cells, and its targeting ability was further improved through fluorouracil modification. The fluorouracil modified AS1411-paclitaxel conjugate with a thioether linker (FASP) exhibited effective targeting of TNBC cells and significantly improved the inhibitory effects on TNBC progression in vitro and in vivo.
CONCLUSIONS
This study successfully developed fluorouracil-modified AS1411-paclitaxel conjugates with a thioether linker for targeted combination chemotherapy in TNBC. These conjugates demonstrated efficient recognition of TNBC cells, enabling targeted delivery and controlled release of paclitaxel and fluorouracil. This approach resulted in synergistic antitumor effects and reduced toxicity in vivo. However, challenges related to stability, immunogenicity, and scalability need to be further investigated for future translational applications.
Topics: Triple Negative Breast Neoplasms; Aptamers, Nucleotide; Humans; Paclitaxel; Nucleolin; Cell Line, Tumor; Animals; Female; Fluorouracil; Drug Liberation; RNA-Binding Proteins; Delayed-Action Preparations; Phosphoproteins; Oligodeoxyribonucleotides; Antineoplastic Combined Chemotherapy Protocols; Mice, Nude; Xenograft Model Antitumor Assays; Cell Proliferation; Oxidation-Reduction; Mice, Inbred BALB C
PubMed: 38951906
DOI: 10.1186/s12967-024-05429-8 -
The Journal of Antibiotics Jul 2024This study was aimed at understanding the distributions of the MICs (minimum inhibitory concentrations) of aztreonam-avibactam, ceftazidime-avibactam and meropenem with...
This study was aimed at understanding the distributions of the MICs (minimum inhibitory concentrations) of aztreonam-avibactam, ceftazidime-avibactam and meropenem with respect to Klebsiella pneumoniae isolates producing different types of carbapenemases and their combinations. K. pneumoniae isolates were collected between 2019 and 2022 from 37 hospitals. PCR was used to screen for bla-, bla- and bla-like genes. MICs were determined by the broth microdilution method for meropenem, aztreonam-avibactam and ceftazidime-avibactam at a constant avibactam concentration of 4 mg l. MIC distributions were analyzed for groups of isolates based on the identified carbapenemases including their combinations. The AZT/AVI MIC and MIC for all NDM-positive isolates were 0.25 and 0.5, respectively, and for serine-carbapenemase-only producers, they were 0.25 and 1 mg l, respectively. The CZD/AVI MIC and MIC values for serine-carbapenemase-only producers were 1 and 4 mg l, respectively. The AZT/AVI MIC and MIC values for co-producers and single carbapenemase producers were the same (i.e., 0.25 and 1 mg l, respectively). The total proportion of meropenem-susceptible isolates (≤8 mg l) among all the carbapenemase producers was 25.1% (31.1% among single-carbapenemase producers and 9.2% among co-producers). The results support the use of aztreonam-avibactam for the empirical treatment of infections caused by any carbapenemase producers.
PubMed: 38951709
DOI: 10.1038/s41429-024-00758-8 -
Clinical Pharmacokinetics Jun 2024Trifluridine/tipiracil, registered for the treatment of patients with metastatic gastric and colorectal cancer, is a substrate and inhibitor for the organic cation...
BACKGROUND AND OBJECTIVES
Trifluridine/tipiracil, registered for the treatment of patients with metastatic gastric and colorectal cancer, is a substrate and inhibitor for the organic cation transporter 2 (OCT2) and the multidrug and toxin extrusion protein 1 (MATE1), which raises the potential for drug-drug interactions with other OCT2/MATE1 modulators. Therefore, we prospectively examined the effect of an OCT2/MATE1 inhibitor (cimetidine) and substrate (metformin) on the pharmacokinetics of trifluridine.
METHODS
In this three-phase crossover study, patients with metastatic colorectal or gastric cancer were sequentially treated with trifluridine/tipiracil alone (phase A), trifluridine/tipiracil concomitant with metformin (phase B) and trifluridine/tipiracil concomitant with cimetidine (phase C). The primary endpoint was the relative difference in exposure of trifluridine assessed by the area under the curve from timepoint zero to infinity. A > 30% change in exposure was considered clinically relevant. A p-value of < 0.025 was considered significant because of a Bonferroni correction.
RESULTS
Eighteen patients were included in the analysis. Metformin did not significantly alter the exposure to trifluridine (- 12.6%; 97.5% confidence interval - 25.0, 1.8; p = 0.045). Cimetidine did alter the exposure to trifluridine significantly (+ 18.0%; 97.5% confidence interval 4.5, 33.3; p = 0.004), but this increase did not meet our threshold for clinical relevance. Metformin trough concentrations were not influenced by trifluridine/tipiracil.
CONCLUSIONS
Our result suggests that the OCT2/MATE1 modulators cimetidine and metformin can be co-administered with trifluridine/tipiracil without clinically relevant effects on drug exposure.
CLINICAL TRIAL REGISTRATION
NL8067 (registered 04-10-2019).
PubMed: 38951433
DOI: 10.1007/s40262-024-01390-3