Therapeutic drug monitoring of perampanel in children diagnosed with epilepsy: Focus on influencing factors on the plasma concentration-to-dose ratio.

OBJECTIVE: This study aimed to investigate the efficacy and tolerability of perampanel (PER) therapy and to optimize a specific plasma reference range for PER in children. Another major aim was to evaluate the potential determinators of PER concentration. METHODS: Concentrations obtained from 80 children were analyzed for routine therapeutic drug monitoring (TDM) between 2021 and 2022. We retrospectively reviewed the clinical data of these patients and assessed the efficacy at 3 months after treatment initiation. Trough concentration-to-dose ratio (C0 /Dose ratio) of PER was compared among patients on various potential influencing factors. RESULTS: A 3-month PER therapy produced a ≥50% reduction in seizure frequency in 58.8% of patients. Twelve patients reported at least one adverse effect (AE), mainly dizziness. The monitoring data showed that the median C0 was 325.5 ng/mL. Under maintenance dosages, approximately 75% of the C0 values were 180.0-610.0 ng/mL. The C0 /Dose ratio in patients aged 1 to <4 was significantly lower by twofold than in those aged 4 to ≤12 years (P = 0.001). Enzyme-inducing ASMs (EIASMs) decreased the C0 /Dose ratio of PER by 25.9% (P = 0.165). In addition, seizure frequency reduction in responders was achieved at a median PER C0 value of 357 ng/mL, which was similar to the value of 314 ng/mL found in nonresponders (P = 0.288). No significant difference was found in PER C0 values between patients with and without AEs (P = 0.082). SIGNIFICANCE: In this study, PER treatment showed acceptable efficacy and tolerance in Chinese children with epilepsy. Contributing factors like age to variable C0 /Dose ratios were identified, and complex PER-ASMs interactions were observed. Notably, the reference range, that is, 180.0-610.0 ng/mL, for routine PER monitoring may be more applicable for them. Routine TDM should be considered a positive attempt to manage the effectiveness and safety of PER.

Novel Fluorescent Probe toward Fe3+ Based on Rhodamine 6G Derivatives and Its Bioimaging in Adult Mice, Caenorhabditis elegans, and Plant Tissues.

A new fluorescent probe LXY based on the rhodamine 6G platforms has been designed, synthesized, and characterized, which could recognize Fe3+ effectively in HEPES buffer (10 mM, pH = 7.4)/CH3CN (2:3, v/v). And the distinct color change and the rapid emergence of fluorescence emission at 550 nm achieved "naked eye" detection of Fe3+. The interaction mode between them was achieved by Job's plot, MS, SEM, and X-ray single-crystal diffraction. Importantly, the crystal structures proved that Fe3+ could induce the rhodamine moiety transform the closed-cycle form to the open-cycle form. But it is interesting that Fe3+ did not appear in the crystal structures. Meanwhile, the limit of detection (LOD) of LXY to Fe3+ was calculated to be 3.47 × 10-9. In addition, the RGB experiment, test papers, and silica gel plates all indicated that the probe LXY could be used to distinguish Fe3+ quantitatively and qualitatively on-site. Moreover, the probe LXY has also been successfully applied to Fe3+ image in Caenorhabditis elegans, adult mice, and plant tissues. Thus, LXY was considered to have some potential for application in bioimaging.

Establishment of a human primary pancreatic cancer mouse model to examine and investigate gemcitabine resistance.

Pancreatic cancer is one of the most fatal types of cancer and is associated with a dismal prognosis. Gemcitabine-based chemotherapy is clinically used for the treatment of advanced pancreatic cancer. However, many forms of pancreatic cancer have acquired resistance to gemcitabine. In order to prevent patients from suffering from the side effects of chemotherapy and to have the chance to receive more effective intervention, assessment of whether the patient pancreatic cancer cells are resistant to gemcitabine before clinical practice is crucial. Recently, patient-derived xenograft (PDX) models have been regarded as a practical approach for preclinical drug resistance test. In the present study, we harvested tumor specimens from 28 pancreatic cancer patients to establish PDX models. The tumor formation rate of the xenografts was 100%, several of which could be re-implanted in nude mice for more than 10 passages. Primary cells were further obtained from the PDX xenografts to determine their morphological features and evaluate their proliferation rate, migration capacity and angiopoietic ability. In addition, the sensitivities of the primary cells and PDX xenografts to gemcitabine were correlated with each other. When compared to the gemcitabine-sensitive cells, the gemcitabine-resistant cells had a higher level of MCF2L expression, suggesting that MCF2L plays an important role in gemcitabine resistance.

[Analysis and Design of Interference Imaging System in Fourier Transform Imaging Spectrometer Based on Multi-Micro-Mirror].

To realize the static state and high throughput of Fourier transform imaging spectrometer (FTIS), a temporal spatial mixed modulated FTIS based on multi-micro-mirror was put forward in this paper, whose interference system was based on Michelson interferometer with a multi-micro-mirror to replace the plane mirror. The remarkable characteristics of this FTIS were no movable parts and slit existing in this system, and the interferogram and image of object could be gained at the same time. The fore-optics system imaged the object on the plane mirror and multi-micro-mirror of the interference system, due to the structure feature of multi-micro-mirror, the optical path difference (OPD) of two imaging beam could be modulated. Through the reimaging system, the image of object with different interference order could be obtained. By means of the analysis to the spectrum signal-to-noise ratio (SNR) of interference system, the relationship between spectrum SNR and image SNR was definite, and the characteristic parameters of multi-micro-mirror were determined. To ensure the constancy of OPD corresponding to each step plane, by means of the analysis to the imaging process of fore-optics system, the optical path structure of telecentric in image space was determined. According to the calculation of the relationship between field of view and OPD, the design indexes of fore-optics system were determined and the optical design was completed. To ensure no extra OPD was introduced by reimaging system, through the analysis of the imaging feature by reimaging system, the optical path structure of double telecentric was determined. According to the calculation of the relationship between incidence aperture angle and step number, the optical system that satisfied the system requirement was designed. By means of the theory analysis and optical design to each unit system, this research can provide a novel development strategy for static and high throughput FTIS.

[Study on transmission efficiency of interference system in spatially modulated Fourier transform spectrometer].

The reflection of the optic system surface and the absorption of the infrared material could reduce the transmission of the incident light in spatially modulated Fourier transform infrared spectrometer. Through the calculation of the transmission function of the interference system and the simulation of the interferogram image and recovered spectrum affected by transmission function, it was indicated that the contrast of the interferogram image declined and the spectral line intensity weakened. The theoretical analysis shows that the contrast of the interferogram image was related to the intensity reflectance of the anti-reflection film, and the attenuation of the spectrum was determined by transmission efficiency concerned with intensity reflectance R1 of the anti-reflection film, intensity reflectance R2 of the beam splitter film, and the absorption coefficient. By means of the analysis and argumentation, the absorption of the material could be ignored in our investigative wave band. So the transmission efficiency was determined only by R1 and R2. Then taking the transmission efficiency as the design target, according to the transmission required by system, the tolerance of the R1 and R2 could be gained.

GA3, a new gambogic acid derivative, exhibits potent antitumor activities in vitro via apoptosis-involved mechanisms.

AIM: Gambogic acid (GA) is the major active ingredient of gamboge, which is secreted from a Chinese traditional medicine, Garcinia hanburyi, which possesses potent antitumor activity. GA3, a new GA derivative, has been shown to possess better water solubility than GA. The aim of the present study was to examine the antitumor activity of GA3 and the mechanism underlying it. METHODS: The growth inhibition of cancer cell lines induced by GA3 was assessed using the SRB assay. DAPI staining, flow cytometry, a DNA fragment assay, and Western blot analysis were used to study the apoptotic mechanisms of GA3. RESULTS: GA3 displayed wide cytotoxicity in diversified human cancer cell lines with a mean IC(50) value of 2.15 micromol/L. GA3 was also effective against multidrug resistant cells, with an average resistance factor (RF) that was much lower than that of the reference drug, doxorubicin. Mechanistic studies revealed that GA3-induced apoptosis in HL-60 cells proceeded via both extrinsic and intrinsic pathways, with caspase-8 functioning upstream of caspase-9. In addition, GA3-driven apoptotic events were associated with up-regulation of Bax, down-regulation of Bcl-2 and cleavage of Bid. Moreover, GA3 triggered cytochrome c release from the mitochondria, in particular bypassing the involvement of the mitochondrial membrane potential. CONCLUSION: Better solubility and a potential anti-MDR activity, combined with a comparable antitumor efficacy, make GA3 a potential drug candidate in cancer therapy that deserves further investigation.

R16, a novel amonafide analogue, induces apoptosis and G2-M arrest via poisoning topoisomerase II.

Amonafide, a naphthalimide derivative, although selected for exploratory clinical trials for its potent anticancer activity, has long been challenged by its unpredictable side effects. In the present study, a novel amonafide analogue, 2-(2-dimethylamino)-6-thia-2-aza-benzo-[def]-chrysene-1,3-diones (R16) was synthesized by substituting 5'-NH(2) of the naphthyl with a heterocyclic group to amonafide, with additional introduction of a thiol group. In a panel of various human tumor cell lines, R16 was more cytotoxic than its parent compound amonafide. It was also effective against multidrug-resistant cells. Importantly, the i.p. administration of R16 inhibited tumor growth in mice implanted with S-180 sarcoma and H(22) hepatoma. The molecular and cellular machinery studies showed that the R16 functions as a topoisomerase II (topo II) poison via binding to the ATPase domain of human topo IIalpha. The superior cytotoxicity of R16 to amonafide was ascribed to its potent effects on trapping topo II-DNA cleavage complexes. Moreover, using a topo II catalytic inhibitor aclarubicin, ataxia-telangiectasia-mutated (ATM)/ATM- and Rad3-related (ATR) kinase inhibitor caffeine and topo II-deficient HL-60/MX2 cells, we further showed that R16-triggered DNA double-strand breaks, tumor cell cycle arrest, and apoptosis were in a topo II-dependent manner. Taken together, R16 stood out by its improved anticancer activity, appreciable anti-multidrug resistance activities, and well-defined topo II poisoning mechanisms, as comparable with the parent compound amonafide. All these collectively promise the potential value of R16 as an anticancer drug candidate, which deserves further development.