The importance of plasma protein binding (PPB) in modulating the effective drug concentration at pharmacological target sites has been the topic of significant discussion and debate amongst drug ...development groups over the past few decades. Free drug theory, which states that in absence of energy-dependent processes, after steady state equilibrium has been attained, free drug concentration in plasma is equal to free drug concentration at the pharmacologic target receptor(s) in tissues, has been used to explain pharmacokinetics/pharmacodynamics relationships in a large number of cases. Any sudden increase in free concentration of a drug could potentially cause toxicity and may need dose adjustment. Free drug concentration is also helpful to estimate the effective concentration of drugs that potentially can precipitate metabolism (or transporter)-related drug–drug interactions. Disease models are extensively validated in animals to progress a compound into development. Unbound drug concentration, and therefore PPB information across species is very informative in establishing safety margins and guiding selection of First in Human (FIH) dose and human efficacious dose. The scope of this review is to give an overview of reported role of PPB in several therapeutic areas, highlight cases where PPB changes are clinically relevant, and provide drug metabolism and pharmacokinetics recommendations in discovery and development settings.
Transport of macromolecules across the blood-brain-barrier (BBB) requires both specific and nonspecific interactions between macromolecules and proteins/receptors expressed on the luminal and/or the ...abluminal surfaces of the brain capillary endothelial cells. Endocytosis and transcytosis play important roles in the distribution of macromolecules. Due to the tight junction of BBB, brain delivery of traditional therapeutic proteins with large molecular weight is generally not possible. There are multiple pathways through which macromolecules can be taken up into cells through both specific and nonspecific interactions with proteins/receptors on the cell surface. This review is focused on the current knowledge of receptor-mediated endocytosis/transcytosis and brain delivery using the Angiopep-2-conjugated system and the molecular Trojan horses. In addition, the role of neonatal Fc receptor (FcRn) in regulating the efflux of Immunoglobulin G (IgG) from brain to blood, and approaches to improve the pharmacokinetics of therapeutic biologics by generating Fc fusion proteins, and increasing the pH dependent binding affinity between Fc and FcRn, are discussed.
Locally advanced or metastatic urothelial carcinoma is generally incurable and has scarce treatment options, especially for cisplatin-ineligible patients previously treated with PD-1 or PD-L1 ...therapy. Enfortumab vedotin is an antibody–drug conjugate directed at Nectin-4, a protein highly expressed in urothelial carcinoma. We aimed to evaluate the efficacy and safety of enfortumab vedotin in the post-immunotherapy setting in cisplatin-ineligible patients.
EV-201 is a multicentre, single-arm, phase 2 study of enfortumab vedotin in patients with locally advanced or metastatic urothelial carcinoma previously treated with PD-1 or PD-L1 inhibitors. Cohort 2 included adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status score of 2 or less who were considered ineligible for cisplatin at enrolment and who had not received platinum-containing chemotherapy in the locally advanced or metastatic setting. Enfortumab vedotin was given intravenously at a dose of 1·25 mg/kg on days 1, 8, and 15 of every 28-day cycle. The primary endpoint was confirmed objective response rate per Response Evaluation Criteria in Solid Tumours version 1.1 assessed by blinded independent central review. Efficacy and safety were analysed in all patients who received at least one dose of enfortumab vedotin. EV-201 is an ongoing study and the primary analysis is complete. This study is registered with Clinicaltrials.gov, NCT03219333.
Between Oct 8, 2017, and Feb 11, 2020, 91 patients were enrolled at 40 sites globally, of whom 89 received treatment. Median follow-up was 13·4 months (IQR 11·3–18·9). At data cutoff (Sept 8, 2020), the confirmed objective response rate was 52% (46 of 89 patients; 95% CI 41–62), with 18 (20%) of 89 patients achieving a complete response and 28 (31%) achieving a partial response. 49 (55%) of 89 patients had grade 3 or worse treatment-related adverse events. The most common grade 3 or 4 treatment-related adverse events were neutropenia (eight 9% patients), maculopapular rash (seven 8% patients), and fatigue (six 7% patients). Treatment-related serious adverse events occurred in 15 (17%) patients. Three (3%) patients died due to acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndrome (one 1% each) within 30 days of first dose and these deaths were considered by the investigator to be related to treatment; a fourth death from pneumonitis occurred more than 30 days after the last dose and was also considered to be related to treatment.
Treatment with enfortumab vedotin was tolerable and confirmed responses were seen in 52% of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma who were previously treated with PD-1 or PD-L1 inhibitors. These patients have few treatment options, and enfortumab vedotin could be a promising new therapy for a patient population with a high unmet need.
Astellas Pharma Global Development and Seagen.
Breast cancer (BC) is the most common malignant tumor in women worldwide, which seriously threatens women's physical and mental health. In recent years, photodynamic therapy (PDT) has shown ...significant advantages in cancer treatment. PDT involves activating photosensitizers with appropriate wavelengths of light, producing transient levels of reactive oxygen species (ROS). Compared with free photosensitizers, the use of nanoparticles in PDT shows great advantages in terms of solubility, early degradation, and biodistribution, as well as more effective intercellular penetration and targeted cancer cell uptake. Under the current circumstances, researchers have made promising efforts to develop nanocarrier photosensitizers. Reasonably designed photosensitizer (PS) nanoparticles can be achieved through non-covalent (self-aggregation, interfacial deposition, interfacial polymerization or core-shell embedding and physical adsorption) or covalent (chemical immobilization or coupling) processes and accumulate in certain tumors through passive and/or active targeting. These PS loading methods provide chemical and physical stability to the PS payload. Among nanoparticles, metal nanoparticles have the advantages of high stability, adjustable size, optical properties, and easy surface functionalization, making them more biocompatible in biological applications. In this review, we summarize the current development and application status of photodynamic therapy for breast cancer, especially the latest developments in the application of metal nanocarriers in breast cancer PDT, and highlight some of the recent synergistic therapies, hopefully providing an accessible overview of the current knowledge that may act as a basis for new ideas or systematic evaluations of already promising results.
Purpose
The renal clearance of fampridine (Fampyra®, or Ampyra®) significantly exceeds the glomerular filtration rate, suggesting active renal secretion is likely the major elimination pathway. The ...goal of this study was to identify the renal transporters that are involved in the renal active secretion, and elucidate the active renal secretion mechanism of fampridine.
Methods
The uptake of fampridine to HEK-293 cells overexpressing human OCT2, MATE1 or MATE2K was determined in the absence and presence of Cimetidine, the prototypical inhibitor of the transporters. The inhibition potential of fampridine on the renal transporters was evaluated by determining the uptake of TEA and Metformin, the probe substrates of the transporters of OCT2 and MATEs, respectively, in the absence or presence of fampridine.
Results
Significant time- and concentration-dependent uptake of fampridine by human OCT2 was observed. The K
m
and V
max
were determined as 51.0 ± 17.1 μM and 1107 ± 136 pmole/min/10
6
cells, respectively. Fampridine also inhibited OCT2 mediated uptake of Metformin with estimated IC
50
of 66.8 μM. In contrast, there was not significant uptake of fampridine by human MATE1 or MATE2K, and fampridine did not inhibit MATE1 or MATE2K mediated uptake of TEA.
Conclusion
The studies indicated fampridine is a substrate and inhibitor of OCT2, but not MATE1 or MATE2K. Results from the study suggested the active renal secretion of fampridine is mediated by human OCT2 but not MATE1 or MATE2K. To our knowledge, fampridine is the first reported substrate specific to OCT2 but not to MATE1 or MATE2K.
At present, it is commonly believed that tRFs and tiRNAs are formed by the specific and selective shear of tRNAs under certain pressure stimulation, rather than by random degradation of tRNA. tRFs ...and tiRNAs have been reported to contribute to the biological process of a variety of human cancers. However, the evidence for the mechanisms of tRFs and tiRNAs in the occurrence and development of gastric cancer (GC) is still insufficient. Here, we aimed to explore the carcinogenic roles of tRFs and tiRNAs in GC with RNA-sequencing technique, and found a novel 3'tRNA-derived fragment tRF-Val was significantly upregulated in GC tissues and cell lines. tRF-Val expression was positively correlated with tumor size and the depth of tumor invasion in GC tissues. Functionally, tRF-Val promoted proliferation and invasion, and inhibited apoptosis in GC cells. Mechanistically, tRF-Val directly bound to the chaperone molecule EEF1A1, mediated its transport into the nucleus and promoted its interaction with MDM2 (a specific p53 E3 ubiquitin ligase), thus inhibiting the downstream molecular pathway of p53 and promoting GC progression. These findings provided a new potential therapeutic target for GC and a new explanation for the occurrence of GC.
In this paper, we develop and put into practice an automatic optical inspection (AOI) system based on machine vision to check the holes on a printed circuit board (PCB). We incorporate the hardware ...and software. For the hardware part, we combine a PC, the three-axis positioning system, a lighting device, and charge-coupled device cameras. For the software part, we utilize image registration, image segmentation, drill numbering, drill contrast, and defect displays to achieve this system. Results indicated that an accuracy of 5 μm could be achieved in errors of the PCB holes allowing comparisons to be made. This is significant in inspecting the missing, the multi-hole, and the incorrect location of the holes. However, previous work only focuses on one or other feature of the holes. Our research is able to assess multiple features: missing holes, incorrectly located holes, and excessive holes. Equally, our results could be displayed as a bar chart and target plot. This has not been achieved before. These displays help users to analyze the causes of errors and immediately correct the problems. In addition, this AOI system is valuable for checking a large number of holes and finding out the defective ones on a PCB. Meanwhile, we apply a 0.1-mm image resolution, which is better than others used in industry. We set a detecting standard based on 2-mm diameter of circles to diagnose the quality of the holes within 10 s.
Objectives
To analyse clinical and radiological changes from disease onset to exacerbation in coronavirus infectious disease-19 (COVID-19) patients.
Methods
We reviewed clinical histories of 276 ...patients with confirmed COVID-19 pneumonia and extracted data on patients who met the diagnostic criteria for COVID-19 severe/fatal pneumonia and had an acute exacerbation starting with mild or common pneumonia.
Results
Twenty-four patients were included. Of these, 8% were smokers, 54% had been to Wuhan, and 46% had comorbidities. Before acute exacerbation, elevated lactate dehydrogenase (232.9 ± 88.7) was present, and chest CT scans showed the number of involved lobes was 4 (2–5) and total CT score was 6 (2–8). Following acute exacerbation, patients were likely to have more clinical symptoms (
p
< 0.01) and abnormal laboratory changes (
p
< 0.01). The number of involved lobes and CT score after an exacerbation significantly increased to 5 (5–5) and 12 (9–14), respectively. Receiver operating characteristic (ROC) curve showed that, when the cutoff value of CT score was 5, the sensitivity and specificity for severe pneumonia were 90% and 70%, respectively. CT findings of ground glass opacity with consolidations (91.7%), bilateral distribution (100.0%), and multifocal lesion (100.0%) were features in found in patients after exacerbation.
Conclusions
There are significant changes in clinical, laboratory, and CT findings in patients from disease onset to exacerbation. An increase in the number of involved lobes or an increased CT score from the baseline may predict poor clinical outcomes. Combining an assessment of CT changes with clinical and laboratory changes could help clinical teams evaluate the prognosis.
Key Points
• The common chest CT signs of COVID-19 pneumonia after exacerbation were ground glass opacity (GGO) with consolidation, bilateral distribution, and multifocal lesions.
• An increase in number of involved lobes or an increased CT score from the baseline may predict a poor clinical outcome.
• Worsened symptoms and abnormal laboratory results are also associated with poor prognosis.
•Various MISGs were prepared and coated on an AuNP film to make a LSPR sensor array.•The influence of the MISGs preparation condition to 4 typical organic acids was investigated.•The molecular ...imprinting effect of the MISGs was confirmed by the comparison with NISGs.•The output of the sensor array was analyzed by PCA and LDA.•The MISG-LSPR sensor array showed a high recognition ability on the single and mixed vapors of the organic acids.
Volatile organic acids are important compounds contained in human body odor. The detection and recognition of volatile organic acids in human body odor are significant in many areas. The present study explored a possibility to use localized surface plasmon resonance (LSPR) of Au nanoparticles (AuNPs) and molecularly imprinted sol-gels (MISGs) as the sensitive layer to recognize typical organic acid odorants, propanoic acid (PA), hexanoic acid (HA), heptanoic acid (HPA) and octanoic acid (OA), from human body. The LSPR layer was prepared by vacuum sputtering of AuNPs on a glass substrate and consequently thermal annealing. The sensitive layer was fabricated by spin-coating molecularly imprinted titanate sol-gel on the AuNPs layer. A homemade optical device was developed to detect the change of transmittance, which was caused by the index changes of organic acid vapors where selecting absorbed by the MISG layers. It was found that compared with MISG coated samples, samples coated with non-imprinted sol gel (NISG) shown no responses to any acid vapors. For the MISG coated sensors, the LSPR sensitivity was affected by the spin coating speed. In addition, a sensor array based on MISGs with different templates (HA, HPA and OA) was constructed to detect the organic acids in single and their binary mixtures. The sensor response was analyzed by principal component analysis (PCA) and linear discriminant analysis (LDA). A 100% classification rate was achieved by leave-one-out cross-validation technique for LDA model. This work demonstrated that the MISGs coated LSPR sensor array has a great potential in organic acid odor recognition of human body odor.
PDF
