Safety, tolerability, and pharmacokinetics of oral (S)-oxiracetam in Chinese healthy volunteers: A randomized, double-blind, controlled phase I study.

BACKGROUND AND OBJECTIVE: (S)-oxiracetam is the major active enantiomer of oxiracetam, which is being developed for dementia. This trial was designed to evaluate the safety, tolerability, and pharmacokinetics of oral (S)-oxiracetam in healthy Chinese volunteers. METHODS: A randomized, controlled, double-blind and dose-escalation design was used in this Phase I trial, which consisted of a single-ascending-dose (SAD) study (400-2000 mg) and a multiple-ascending-dose (MAD) study (400-1600 mg). Blood, urine and feces samples were collected for pharmacokinetic analysis. Safety was evaluated by monitoring adverse events (AEs). RESULTS: AEs in both studies were mild or moderate in severity and dose-independent. In the SAD study, no chiral transformation was observed. 55.03% and 36.16% of (S)-oxiracetam was excreted unchanged in urine and feces, respectively. Exposures exhibited dose-proportional increases over the range of 400 to 1600 mg but almost unchanged from 1600 to 2000 mg. (S)-oxiracetam was absorbed rapidly, reaching a peak at 0.75-1.00 h, and t1/2 was 6.12-6.60 h. Food had no effect on AUC, but prolonged Tmax to 3.00 h. In the MAD study, steady-state was observed on day 5. Mild accumulations were observed after 7 days of repeated dosing. CONCLUSION: (S)-oxiracetam was safe and tolerated with favorable pharmacokinetic profiles at all study doses, providing dosing evidence for further efficacy evaluation.

Pharmacokinetics and Bioequivalence of Fudosteine in Healthy Chinese Volunteers Under Fasting and Fed Conditions: A 4-Way Replicate Crossover Study.

The bioequivalence of a generic fudosteine tablet vs a brand-named fudosteine tablet under fasting and fed conditions was evaluated in this study. This randomized, open-label, single-dose, 4-way replicate, crossover, bioequivalence study included 64 healthy Chinese subjects (fasting cohort, n = 32; fed cohort, n = 32) who were assigned to receive a single 200-mg dose of generic or brand-named fudosteine. Blood samples were collected before dosing and up to 24 hours after dosing. The plasma concentrations of fudosteine were analyzed by high-performance liquid chromatography-tandem mass spectrometry. Safety was monitored. There were no significant differences in maximum plasma concentration (Cmax ), area under the plasma concentration-time curve (AUC) from time 0 to time t (AUC0-t ), or AUC from time 0 to infinity (AUC0-∞ ) between the test and reference formulations. However, food showed a significant effect on Cmax , AUC0-t , and AUC0-∞ for both generic and brand-named fudosteine. The 90%CIs of the test/reference ratios of Cmax , AUC0-t, and AUC0-∞ were within the range of 80% to 125% under both fasting and fed conditions. No serious adverse events were reported. The bioequivalence between generic and brand-named fudosteine under fasting and fed conditions was demonstrated. Both of them had good tolerance for healthy Chinese volunteers. In addition, food delayed the absorption of fudosteine, so taking this medicine before meals might be an optimized option.

IL-37 inhibits glycolysis of lung adenocarcinoma by inhibiting the expression of PFKFB3.

Aerobic glycolysis is one of the hallmarks of cancer. The metabolic phenotype of tumor cells is characterized by preferential dependence on glycolysis under aerobic conditions. Recent researchers have provided a piece of information on the effectiveness of targeting glycolysis. Thus, targeted glucose metabolism therapy is still a research hotspot. Interleukin 37 (IL-37) plays an important role in tumor development. Previous studies have found that IL-37 can inhibit the progression of lung adenocarcinoma in a variety of ways. For example, IL-37 can inhibit the migration and invasion of lung adenocarcinoma by inhibiting the interleukin 6(IL-6)/ Signal transducing activator of transcription 3(STAT3) pathway. IL-37 inhibits tumor growth by regulating RNA methylation at the M6A site of lung adenocarcinoma. It has been found that overexpression of IL-37 in macrophages can reverse the Warburg effect. The mechanism of IL-37 on glucose metabolism of tumor cells has not been studied. In research, glucose uptake and lactic acid production were inhibited in A549 cells with recombinant human IL-37(rhIL-37). Also, rhIL-37 inhibited the expression level of PFKFB3 in A549 cells. To verify whether the two aspects of rhIL-37's effects on A549 cells are related, we applied PFK15, a specific inhibitor of PFKFB3, to prove that rhIL-37 inhibits the glucose uptake and lactate production of A549 cells by inhibiting the expression of PFKFB3, and further inhibits the progression of lung adenocarcinoma.

Accurate detection of lung cancer-related microRNA through CRISPR/Cas9-assisted garland rolling circle amplification.

Background: MicroRNA (miRNA) is reported to be closely related to a variety of pathophysiological processes for carcinoma and considered a potential biomarker for the diagnosis of lung cancer with brain metastasis. However, developing an accurate and sensitive miRNA detection method has proven to be a challenge. The aim of the present study was to integrate the advantages of rolling circle amplification (RCA), clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated nucleases 9 (Cas9), and catalytic hairpin assembly (CHA) technologies to develop an miRNA detection method. Methods: In the present study, we developed a novel approach for the sensitive and accurate detection of miRNA through integrating garland RCA and CRISPR/Cas9-assisted signal generation. In this method, target miRNA cyclized dumbbell padlock and triggered the RCA process to form long single-stranded DNA products with a repeated hairpin structure. Double-stranded DNA sequences (dsDNA) were formed with the addition of complementary sequences. With the assistance of the Cas9 enzyme for specific recognition and cleavage of formed dsDNA, RCA products were disassembled into hairpin probes. The generated hairpin probe could be unfolded by target miRNA to initiate the CHA process for signal generation. Results: Through integration of the RCA and CHA processes, the method demonstrated favorable detection performance. The correlation equation between the signal and concentration of target miRNA was determined to be Y=312.3 × lgC + 2108, with a high correlation coefficient of 0.9786. The approach also exhibited high selectivity to the mismatched miRNAs. Conclusions: Our method could be used in the screening, diagnosis, and prognosis of multiple diseases without complicated thermal cycling instrumentation.

Reduction in C-Peptide Levels and Influence on Pharmacokinetics and Pharmacodynamics of Insulin Preparations: How to Conduct a High-Quality Euglycemic Clamp Study.

Objective: The aim of the study was to investigate the different extent of inhibition of endogenous insulin secretion by the reduction of C-peptide levels in an euglycemic clamp study and its effects on the evaluation of pharmacokinetics, pharmacodynamics of insulin preparations, and quality of clamp study to determine the best reduction range of C-peptide levels. Methods: Healthy Chinese male volunteers were enrolled and underwent a single-dose euglycemic clamp test. Participants were subcutaneously injected with long-acting insulin glargine (0.4 IU/kg). Blood samples were collected pretest and up to 24 h post-test to assess pharmacokinetics (PK), pharmacodynamics (PD), and C-peptide levels. Results: We divided the 39 volunteers enrolled in the study into three groups according to the reduction of C-peptide levels: group A (ratio of C-peptide reduction <30%, n = 13), group B (ratio of C-peptide reduction between ≥ 30% and <50%, n = 15), and group C (ratio of C-peptide reduction ≥50%, n = 11); there were significant differences in the three groups (p = 0.000). The upper and lower limits of blood glucose oscillation in group C was statistically lower than the other groups, the range of oscillating glucose levels in group C was -17.0 ± 6.6% to -1.1 ± 6.7%. The AUC0-24 h in groups A, B, and C were 9.7 ± 2.2, 11.0 ± 2.9, and 11.9 ± 2.1 ng/ml × min, respectively, which indicated an increasing trend in the three groups (P trend = 0.041). For quality assessment, the average glucose (p = 0.000) and MEFTG (p = 0.001) levels in three groups were significantly different. Conclusion: The different extent of inhibition of endogenous insulin will influence the PK/PD of insulin preparations and the quality of the euglycemic clamp. Furthermore, the ratio of C-peptide reduction should be above 50% to free from the interference of endogenous insulin, and the range of blood glucose levels should be consistently maintained at -10% to 0 in the euglycemic clamp.

Highly Efficient Spatial-Temporal Correlation Basis for 5G IoT Networks.

One of the major concerns in 5G IoT networks is that most of the sensor nodes are powered through limited lifetime, which seriously affects the performance of the networks. In this article, Compressive sensing (CS) technique is used to decrease transmission cost in 5G IoT networks. Sparse basis is one of the important steps in the CS. However, most of the existing sparse basis-based method such as DCT (Discrete cosine transform) and DFT (Discrete Fourier Transform) basis do not capture data structure characteristics in the networks. They also do not take into consideration multi-resolution representations. In addition, some of sparse basis-driven methods exploit either spatial or temporal features, resulting in performance degradation of CS-based strategies. To address these challenging problems, we propose a novel spatial-temporal correlation basis algorithm (SCBA). Subsequently, an optimal basis algorithm (OBA) is provided considering greedy scoring criteria. To evaluate the efficiency of OBA, orthogonal wavelet basis algorithm (OWBA) by employing NS (Numerical Sparsity) and GI (Gini Index) sparse metrics is also presented. In addition, we discuss the complexity of the above three algorithms, and prove that OBA has low numerical rank. After experimental evaluation, we found that OBA is capable of the sparsest representing original signal compared to spatial, DCT, haar-1, haar-2, and rbio5.5. Furthermore, OBA has the low recovery error and the highest efficiency.

Temperature-Dependent Photoluminescence of Zn-Cu-In-S Quaternary Nanocrystals with Different Reaction Time.

Non-toxic, environment-benign colloidal ZnCulnS Nanocrystals (ZCIS NCs) were synthesized and the temperature dependence of the photoluminescence (PL) energy, line width, and intensity for the ZCIS NCs with different reaction time were studied in the temperature range from 50 to 280 K. Generally, for typical ZCIS NCs ensemble, it has been constantly observed that the PL peaks energy decrease with the experimental temperature raising and the value of Eg(0) decrease with the increase of reaction time. Furthermore, the full width at half maximums (FWHM) of the PL spectra increased with the experimental temperature raising. It was found that the temperature dependence of the integrated PL intensity of ZCIS NCs decrease with the experimental temperature raising and the intensity decrease much with increasing reaction time.

[Therapeutic effects of rhEPO, rhG-CSF on sulfur mustard induced toxicity in dogs].

OBJECTIVE: To evaluate the therapeutic effects of recombinant human erythropoietin (rhEPO) and recombinant human granulocyte colony stimulating factor (rhG-CSF) on sulfur mustard (SM) induced toxicity in dogs. METHODS: Ten dogs were used as the animal model. Control group had four dogs while treatment group had six. Half an hour after subcutaneously injected with 12 mg/kg (body weight) of SM, the dogs of the treatment group were treated by rhEPO, rhG-CSF and other medicines. General examinations of blood were measured before injecting SM and were continually watched for a week after poisoning. RESULTS: Three dogs in control group died in three days after poisoning, dogs in treatment group all survived. WBC of the control group decreased significantly 3 days after poisoning. RBC of the control group had a slight increase at first, then came down. While WBC and RBC of treatment group remained constant. LYM of both groups descended notably right after poisoning, especially in control group. Two days after poisoning, RC in treatment group began to rise and remained at high level for about a week. No obvious changes of RC in control group were found. CONCLUSION: The use of rhEPO and rhG-CSF after SM exposure can stimulate the growth of the erythrocyte, reticulocyte and leucocyte in dogs. Therefore, rhEPO and rhG-CSF may be significant assistant drugs in future experiment of SM.