Bioequivalence study of two formulations of afatinib dimaleate tablets in healthy subjects under fasting conditions: A randomized, open-label, single-dose, crossover trial.

OBJECTIVE: To evaluate the bioequivalence of two different afatinib dimaleate formulations in healthy Chinese subjects under fasting conditions and to assess their pharmacokinetic and safety profiles. MATERIALS AND METHODS: This randomized, open-label, 2-period, crossover, bioequivalence study included 32 healthy Chinese subjects. The subjects were assigned to receive a single 40-mg dose of generic or brand-named afatinib dimaleate tablet. Blood samples were collected pre-dose and up to 120 hours after dosing. Healthy subjects orally took the trial preparation (T) (afatinib maleate tablets developed by Jiangxi Shanxiang Pharmaceutical Co., Ltd., Gan Zhou, China) and the reference preparation (R) (afatinib maleate tablets developed by Boehringer Ingelheim Pharma GmbH & Co., Ingelheim, Germany) under fasting conditions in the appropriate period according to the randomization. We measured the blood concentrations, calculated the pharmacokinetic parameters of the two preparations in the human body, and evaluated whether formulations were bioequivalent. Safety of the preparations in healthy subjects was monitored during the whole trial. Safety assessment was conducted by vital signs, physical examination, laboratory examination, and 12-lead electrocardiogram during the study, i.e., from the time the subject received the test drug to the end of the last visit. RESULTS: Under fasting conditions, the 90% confidence intervals (CIs) of the geometric mean ratios of the test/reference for afatinib dimaleate were 93.34 - 103.92% for AUC0-t, 90.26 - 105.52% for Cmax, and 93.49 - 104.05% for AUC0-∞. CONCLUSION: The 90% CI for the geometric mean ratios (test/reference) of Cmax, AUC0-t, and AUC0-∞ were within the range of 80.00 - 125.00%, indicating that the test formulation was equivalent to the reference formulation in healthy Chinese subjects under fasting conditions. Both products were similar in terms of safety.

[Comparison on blood-prostate barrier permeability of tanshinone extract and corresponding major monomers].

In this study, the transmittance of tanshinone Ⅱ_A(Tan Ⅱ_A) and cryptotanshinone(CTS) through the blood-prostate barrier and their distributions in the prostate tissue were compared between tanshinone extract(Tan E) treatment group and the corresponding monomer composition group under the equivalent dose conversion in vitro and in vivo. First, the human prostate epithelial cell line RWPE-1 was cultured in vitro for 21 days for the establishment of a blood-prostate barrier model, and the transmission of Tan Ⅱ_A and CTS through the barrier model was investigated after administration of Tan E and corresponding single active components. Second, SD rats were administrated with 700 mg·kg~(-1) Tan E, 29 mg·kg~(-1) CTS, and 50 mg·kg~(-1) Tan Ⅱ_A by gavage, and plasma and prostate tissue samples were collected at the time points of 2, 4, 8, 12, and 24 h. The Tan Ⅱ_A and CTS concentrations in the samples were determined. The results showed that in the cell model, the cumulative transmission amounts of CTS and Tan Ⅱ_A in the extract at each time point were higher than those of the corresponding single active components(P<0.01). In rats, after the administration of Tan E, the concentrations of Tan Ⅱ_A and CTS in rat plasma and prostate were higher than those of the corresponding single active components. This study demonstrated that the coexisting components in Tan E promoted the penetration of its main pharmacological components Tan Ⅱ_A and CTS through the blood-prostate barrier. The findings provide a theoretical and experimental basis for the application of Tan E in the clinical treatment of prostate-related diseases.

A Predefined-Time Control for the Laser Acquisition in Space Gravitational Wave Detection Mission.

The establishment of a laser link between satellites, i.e., the acquisition phase, is a key technology for space-based gravitational detection missions, and it becomes extremely complicated when the long distance between satellites, the inherent limits of the sensor accuracy, the narrow laser beam divergence and the complex space environment are considered. In this paper, we investigate the laser acquisition problem of a new type of satellite equipped with two two-degree-of-freedom telescopes. A predefined-time controller law for the acquisition phase is proposed. Finally, a numerical simulation was conducted to demonstrate the effectiveness of the proposed controller. The results showed that the new strategy has a higher efficiency and the control performance can meet the requirements of the gravitational detection mission.

Humanistic outcomes in treatment resistant depression: a secondary analysis of the STAR*D study.

BACKGROUND: In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, a third of patients did not achieve remission or adequate response after two treatment trials, fulfilling requirements for treatment resistant depression (TRD). The present study is a secondary analysis of the STAR*D data conducted to compare the humanistic outcomes in patients with TRD and non-TRD MDD. METHODS: Patients with major depressive disorder who entered level 3 of the STAR*D were included in the TRD group, while patients who responded to treatment and entered follow-up from level 1 or 2 were included in the non-TRD group. The first visit in level 1 was used for baseline assessments. The time-point of assessments for comparison was the first visit in level 3 for TRD patients (median day: 141), and the visit closest to 141 ± 60 days from baseline for non-TRD patients. Outcomes were assessed by the 12-item Short Form Health Survey (SF12), 16-item Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), Work and Social Adjustment Scale (WSAS), and Work Productivity and Activity Impairment scale (WPAI). Scores were compared in a linear model with adjustment for covariates including age, gender, and depression severity measured by the 17-item Hamilton Rating Scale for Depression (HDRS17) and Quick Inventory of Depressive Symptomatology (QIDS). RESULTS: A total of 2467 (TRD: 377; non-TRD: 2090) patients were studied. TRD patients were slightly older (mean age 44 vs 42 years), had a higher proportion of men (49% vs 37%, p < .0001), and baseline depression severity (HDRS17: 24.4 vs 22.0, p < .0001) vs non-TRD patients. During follow-up, TRD patients had lower health-related quality of life (HRQOL) scores on mental (30 vs 45.7) and physical components (47.7 vs 48.9) of the SF12, and lower Q-LES-Q scores (43.6 vs 63.7), greater functional and work impairments and productivity loss vs non-TRD patients (all p < 0.05). CONCLUSION: Patients with TRD had worse HRQOL, work productivity, and social functioning than the non-TRD patients.

Load bearing capacity of arch structure in unconsolidated layers.

Coal mining inevitably results in the movement of overlying strata, with the upward formation of the strata leading to surface subsidence, causing irreversible impact on the buildings, land, and ecological environment. The movement and deformation of the strata are controlled by the bearing structure in the overlying strata, whose failure results in the deformation and breakage of the overlying strata simultaneously. While studies have been conducted on the arch structure in unconsolidated layers (ASUL), its bearing performance has not been addressed. Therefore, this study develops a bearing mechanics model based on the morphological characteristics of the ASUL. The analytical expressions of the axial force, bending moment, and shear force of the cross-sectional area were determined using theoretical derivations. The model analysed the internal forces and showed the influence laws of the overlying load, horizontal pressure coefficient, and rise-to-span ratio of the ASUL. The failure criterion of the bearing was also further determined. The results indicated that with overlying and horizontal loads, the axial force and bending moment are symmetrically distributed, whereas the shear force is asymmetrically distributed. In addition, the axial force gradually increases from the dome to the base of the ASUL. Compared to the axial force and bending moment, the shear force has a lower impact on the stability of the ASUL. Most of the axial force and overlying load is received through the axial compression of the cross-section to maintain stability and play a bearing role on the overlying unconsolidated layers. As the overlying load, horizontal pressure coefficient, and rise-to-span ratio increase, the axial force, bending moment, and shearing force also increase gradually. This effect is more apparent at the dome, spandrel, and base of the ASUL. The stability of the dome and spandrel is key to the overall structural stability. Therefore, the failure criterion for the ASUL was determined based on the compression failure at the dome and spandrel. During the mining process of the working face, the ASUL served as load-bearing control for the overlying unconsolidated layers. Further, increasing width of the working face damages and shifts the base of the ASUL, resulting in compression failure at the dome and spandrel, further inducing dome lift and causing overall failure of the ASUL. Considering the aforementioned factors, a control method that reinforces the surface subsidence of the ASUL by 'one-time, upward, staged, and multiple-ground-drilling' compaction grouting has been proposed. During the mining process of the working face, the arch bead-like structure, combined with the ASUL, serves as the load-bearing control on the overlying strata and ground surface, reducing ASUL deformation in the unconsolidated layers, overlying strata, and ground surface. This process enables the controlling of ground subsidence of coal mining in thick unconsolidated layers.

Numerical simulation of strength and failure analysis of heterogeneous sandstone under different loading rates.

Natural rock masses often contain heterogeneous structures with varying sizes, non-uniform distributions, and strengths, which influence the mechanical response characteristics and crack propagation modes under loading. Furthermore, heterogeneous structures can affect the stability of the rock mass, in serious cases, leading to geotechnical and mining engineering disasters. In the present work, a parallel-bond model (PBM)-based numerical simulation using Particle Flow Code (PFC) was carried out to study the strength and failure characteristics of sandstone specimens with heterogeneous structures under different loading rates. The results show that the peak strength increases with the increasing loading rate. In addition, all of the initial cracks occurred at the edges of the heterogeneous structures of specimens under different loading rates. The greater the loading rate, the greater the stress concentration degree at the edge of the heterogeneous structures, the greater the dissipated energy as the sandstone specimens with heterogeneous structures suffer damage, the more intense the acoustic emission activity, and the greater the damage degree of the specimens. The number of cracks generated in sandstone specimens with heterogeneous structures increases gradually with the increasing loading rate during the initial loading stage, and gradually decreases after the specimens are damaged. Cracks propagate and develop from the upper right region to the lower right region of the specimens, forming crack groups that rapidly penetrate the specimens, leading to failure. Under different loading rates, the final failure behavior of the sandstone specimens with heterogeneous structures changes from an inverted V-type to θ-type, then gradually evolves to O-type failure.

Equivalent magnetic circuit method of estimating iron losses in induction motor spindles.

The iron losses in the motor of motorized spindles have a significant effect on their heat generation, thermal deformation, and machining accuracy. The equivalent magnetic circuit (EMC) method for estimating iron losses in the spindle motor is proposed, where the magnetic flux density distribution of any cross section inside the spindle motor is assumed as a uniform one. A mechanical loss separation method of no load running combined with a sudden loss of power supply is also proposed. The EMC method is verified by prototype experiment and a different analysis method comparison. The EMC does not need to solve complex electromagnetic fields, and to do 2D or 3D eddy current analysis and the corresponding post-processing. There is only need to perform a simple magnetic circuit calculation. Therefore, it can realize a fast analysis and prediction. The proposed mechanical loss separation method requires only one prototype during a whole testing process. There is no need for any other same prototype and a coupling device. It is simpler, and can eliminate the braking torque and electromagnetic losses of the spindle motor.

Infectious bursal disease virus replication is inhibited by avain T cell chemoattractant chemokine CCL19.

Chemokine CCL19, together with its receptor CCR7, is one of the most important factors recruiting immune cells into target organ during virus infection. Our previous study has shown that CCL19 played a vital role in the process of T cell trafficking into bursae during bursal disease virus (IBDV) infection. In this study, we hypothesized that CCL19 could exert direct influences on IBDV replication other than recruiting immune cells. A eukaryotic expression vector of pEGFP-N1/CCL19 was successfully constructed and identified by PCR, double enzymes digestion, and sequencing. Different concentrations of pEGFP-N1/CCL19 plasmids were transfected into DF1 cells and CCL19 protein was highly expressed. Then, DF1 cells were infected with IBDV B87 strain post-transfection. Based on PCR and Western blot results, CCL19 could obviously decrease the gene levels of VP1 and VP2 and the protein levels of VP2 and VP3. When CCL19 was knocked down, the gene levels of VP1 and VP2 were significantly upregulated. Moreover, indirect immunostaining revealed that the IBDV content was largely decreased after CCL19 overexpression. Additionally, CCL19 inhibitory effects might rely on activation of the JNK signal pathway. Taken together, chemokine CCL19 directly blocks IBDV replication in DF1 cells, indicating that CCL19 could play crucial functions other than recruiting T cells during the pathogenesis of IBDV.

[Advances on progesterone receptor gene].

The steroid hormone, progesterone, plays a key role in diverse events associated with female reproduction. In humans and other vertebrates, the biological activity of progesterone is mediated by modulation of the transcriptional activity of two progesterone receptors, PGR-A and PGR-B. This review introduced the structure, expression regulation and polymorphism of progesterone receptor gene. The relationship between progesterone receptor gene and reproductive function was also discussed in mammals.

Healthcare costs associated with rivaroxaban or warfarin use for the treatment of venous thromboembolism.

INTRODUCTION: Rivaroxaban has been shown to have similar efficacy but less major bleeding than warfarin in randomized trials of patients experiencing venous thromboembolism (VTE). This report sought to assess healthcare costs up to 12-months following an index VTE in patients prescribed either rivaroxaban or warfarin. MATERIALS AND METHODS: This study analyzed claims from the MarketScan Commercial Claims and Encounters Database from November 2011-July 2015. It selected adults newly-diagnosed with VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) if they had an outpatient prescription claim for rivaroxaban or warfarin within 7-days of the index event. Warfarin users were 2:1 propensity-score matched to rivaroxaban users and followed until the end of insurance coverage, end of data availability or 12-months of follow-up. Total per patient healthcare costs, including inpatient, outpatient, and overall pharmacy costs, were compared using a multivariable generalized linear model. RESULTS: In total, 10,929 rivaroxaban patients were matched to 21,858 warfarin patients. Mean follow-up for rivaroxaban and warfarin patients was 317- and 321-days for those experiencing an index DVT, and 313- and 318-days for those with PE. Mean overall treatment costs per patient were lower for rivaroxaban vs warfarin users (-$1,116, p = .0016). This cost difference was driven by lower inpatient (-$622) and outpatient (-$1,156) treatment costs, and the higher pharmacy costs ($661) were, therefore, fully offset. Results were similar when analysis was restricted to DVT patients. No significant difference in total costs was observed in patients experiencing an index PE. LIMITATIONS: Claims databases are subject to inaccuracies and missing data. Prescription claims may not fully reflect actual medication utilization. Despite propensity-score matching and regression, residual confounding cannot be excluded. CONCLUSIONS: Rivaroxaban was associated with significantly lower total per patient VTE treatment costs, despite higher pharmacy costs. These savings are the result of decreased inpatient and outpatient healthcare utilization costs associated with rivaroxaban.

Prescribers' behavior following below- versus above-range international normalized ratio values in warfarin-treated deep vein thrombosis patients.

Maintaining acceptable international normalized ratio (INR) control among deep vein thrombosis (DVT) patients taking warfarin is challenging. We evaluated prescribers' behavior to out-of-range INRs in DVT patients following initial INR stabilization. Following INR stabilization, a below-range INR was associated with fewer subsequent measurements and warfarin-dosing adjustments, and a longer time to re-achieve a therapeutic INR compared to an above-range INR.

International normalized ratio stability in warfarin-experienced patients with nonvalvular atrial fibrillation.

BACKGROUND: Maintaining stable levels of anticoagulation using warfarin therapy is challenging. Few studies have examined the stability of the international normalized ratio (INR) in patients with nonvalvular atrial fibrillation (NVAF) who have had ≥6 months' exposure to warfarin anticoagulation for stroke prevention. OBJECTIVE: Our objective was to describe INR control in NVAF patients who had been receiving warfarin for at least 6 months. METHODS: Using retrospective patient data from the CoagClinic™ database, we analyzed data from NVAF patients treated with warfarin to assess the quality of INR control and possible predictors of poor INR control. Time within, above, and below the recommended INR range (2.0-3.0) was calculated for patients who had received warfarin for ≥6 months and had three or more INR values. The analysis also assessed INR patterns and resource utilization of patients with an INR >4.0. Logistic regression models were used to determine factors associated with poor INR control. RESULTS: Patients (n = 9433) had an average of 1.6 measurements per 30 days. Mean follow-up time was 544 days. Approximately 39% of INR values were out of range, with 23% of INR values being <2.0 and 16% being >3.0. Mean percent time with INR in therapeutic range was 67%; INR <2.0 was 19% and INR >3.0 was 14%. Patients with more than one reading of INR >4.0 (~39%) required an average of one more visit and took 3 weeks to return to an in-range INR. Male sex and age >75 years were predictive of better INR control, whereas a history of heart failure or diabetes were predictive of out-of-range INR values. However, patient characteristics did not predict the likelihood of INR >4.0. CONCLUSIONS: Out-of-range INR values remain frequent in patients with NVAF treated with warfarin. Exposure to high INR values was common, resulting in increased resource utilization.

International normalized ratio stabilization in newly initiated warfarin patients with nonvalvular atrial fibrillation.

BACKGROUND: Warfarin is effective for stroke prevention in patients with atrial fibrillation (AF), but international normalized ratio (INR) levels fluctuate and frequent monitoring is necessary. METHODS: This study used data from a large anticoagulation management service database to analyze the relationship between INR stabilization and warfarin utilization for >1 year in patients with nonvalvular AF (NVAF). Anticoagulation records from a large US electronic database collected from 2006 to 2010 were analyzed. RESULTS: Patients with NVAF and ≥ 3 INR values in the dataset were identified (n = 15,276). INR stabilization was defined as the first three consecutive INR values between 2.0 and 3.0 after warfarin initiation. One quarter of patients (n = 3809) failed to reach INR stabilization. After initial stabilization, 30% of subsequent INR values were out of range. The mean (± standard deviation [SD]) follow-up time from stabilization to the end of study for these patients was 494.2 ± 418.1 days. Age ≥ 75 years (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.08-1.27), hypertension (OR = 1.19, 95% CI = 1.10-1.29), or prior stroke (OR = 1.29, 95% CI = 1.04-1.61) were positively associated with achieving stabilization; heart failure was negatively associated with stabilization (OR = 0.78, 95% CI = 0.70-0.87). Male gender (p < 0.0001) and hypertension were associated with earlier stabilization (p = 0.0013); heart failure was associated with later stabilization (p = 0.0098). Patients who achieved INR stabilization within 1 year were 10 times more likely to remain on warfarin than patients who did not achieve it. LIMITATIONS: Observational data may contain incomplete records. Data on adherence, concurrent medications, vitamin K intake, genotype, reasons for discontinuation of monitoring, and patient outcomes were not available in the dataset. The study findings were generalizable only to patients with AF who were managed by anticoagulation clinics. CONCLUSION: Given the importance of stroke prevention among patients with AF, the potential for unpredictable INR patterns should be carefully considered during clinical decision-making.