Pharmacokinetic modeling analysis of cilostazol and its active metabolites (OPC-13015 and OPC-13213) after multiple oral doses of cilostazol in healthy Korean volunteers.

Cilostazol is a selective inhibitor of phosphodiesterase III (PDE III), which is prescribed for patients with peripheral arterial disease, especially intermittent claudication. The purpose of the study was to investigate the pharmacokinetic (PK) of cilostazol and its metabolites on the immediate (IR) formulation of cilostazol in healthy Korean male volunteers by population PK modeling analysis implemented using NONMEM software.A 2 × 2 crossover study comparing multiple oral doses of IR and SR formulations of cilostazol were conducted. Serial plasma concentrations of cilostazol and its active metabolites were used in this analysis.The PK was best depicted by one-compartment model, with absorption kinetics of cilostazol having mixed first- and zero-order kinetics with a time delay at the beginning of absorption. The introduction of interoccasion variabilities into zero-order (D1), first-order (Ka), and relative bioavailability (F1) significantly improved the model fit, and total body water (TBW) was identified as a significant covariate positively affecting the clearance of cilostazol. The model validation suggested that the model constructed in this study predicted the plasma concentration of cilostazol and its two active metabolites reasonably well.The PK model we developed explored the PK characteristics of cilostazol in Korean male subjects, and may be useful for identifying optimal individual dosing regimens of cilostazol.

Humanin rescues cultured rat cortical neurons from NMDA-induced toxicity not by NMDA receptor.

Excitatory neurotoxicity has been implicated in many pathological situations and there is no effective treatment available. Humanin is a 24-aa peptide cloned from the brain of patients with Alzheimer's disease (AD). In the present study, excitatory toxicity was induced by N-methyl-D-aspartate (NMDA) in primarily cultured rat cortical neurons. MTT assessment, lactate dehydrogenase (LDH) release, and calcein staining were employed to evaluate the protective activity of humanin on NMDA induced toxicity. The results suggested that NMDA (100 µmol/L, 2.5 hr) triggered neuronal morphological changes, lactate dehydrogenase (LDH) release (166% of the control), reduction of cell viability (about 50% of the control), and the decrease of living cell density (about 50% of the control). When pretreated with humanin, the toxicity was suppressed. The living cells' density of humanin treated group was similar to that of control. The cell viability was attenuated dose-dependently (IC50 = 0.132 nmol/L). The LDH release was also neutralized in a dose-dependent manner. In addition, the intracellular Ca(2+) overloading triggered by NMDA reverted quickly and humanin could not inhibit it. These findings indicate that humanin can rescue cortical neurons from NMDA-induced toxicity in rat but not through interfering with NMDA receptor directly.

Population pharmacokinetics of FCN-159, a MEK1/2 inhibitor, in adult patients with advanced melanoma and neurofibromatosis type 1 (NF1) and model informed dosing recommendations for NF1 pediatrics.

Objective: FCN-159 is a highly active mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) inhibitor in patients with advanced melanoma and neurofibromatosis type 1 (NF1). We report a population pharmacokinetic (PopPK) model-based analysis of FCN-159 and its application to inform dose selection for NF1 pediatric trials. Methods: PK data collected from patients with advanced melanoma and NF1 in two clinical studies (NCT03932253 and NCT04954001) were analyzed using a non-linear mixed effects model. The adult model was adapted by incorporating allometric scaling for PK projection in 2-17 years old children. Pediatric exposure in different body surface area (BSA) bins was simulated to identify nominal doses (i.e., dose amounts given as integers) and BSA bin cutoffs to achieve exposure comparable to adults' optimal exposure across the entire pediatric BSA range. Results: The final dataset consisted of 45 subjects with a total of 1030 PK samples. The PK of FCN-159 was well-described by a 2-compartment model with first-order linear elimination and delayed first-order absorption. Covariates, including BSA, age, sex, albumin, total protein, and cancer type, were identified as statistically significant predictors of FCN-159 disposition. Simulations based on the final model projected daily doses of 4 mg/m2 QD with optimized BSA bin cutoffs would allow fixed nominal doses within each bin and result in steady state exposure approximating the adult exposure observed at the recommended phase 2 dose (RP2D) in NF1, which is 8 mg QD. Conclusion: The developed population PK model adequately described the PK profile of FCN-159, which was adapted using allometric scaling to inform dose selection for NF1 pediatric trials.

Clinical Effect of Nimodipine Combined with Magnesium Sulfate on Pregnancy-Induced Hypertension Syndrome.

The incidence of pregnancy-induced hypertension in China is 9.4%, which is at a relatively high level. Its serious impact on maternal and infant health is the main reason for maternal and perinatal morbidity and mortality. There are many factors affecting pregnancy-induced hypertension. The incidence of pregnancy-induced hypertension is different due to different levels of cultural knowledge, health awareness, economic income, nutrition, and medical support. Since its etiology has not been elucidated thus far, there is no known treatment of the disease, and the main principles are spasmolysis, hypotension, expansion, and timely termination of pregnancy. Observe the effect of nimodipine combined with magnesium sulfate on serum heat shock protein 70 (HSP70) and pentamer 3 (PTX3) levels in patients with pregnancy-induced hypertension. Ninety-six patients with pregnancy-induced hypertension syndrome admitted to our hospital from May 2016 to February 2019 are selected and randomly divided into two groups according to the 1 : 1 principle, with 48 cases in each group. The single drug group is treated with magnesium sulfate, and the combined group is treated with nimodipine combined with magnesium sulfate. Changes in blood pressure, HSP70, PTX3, placental growth factor (PLGF), and vascular endothelial cell injury markers are recorded in the two groups, and adverse reactions and pregnancy outcomes are observed. After treatment, the blood pressure and levels of HSP70, PTX3, endothelin-1 (ET-1), and nitric oxide (NO) in the two groups decreased, and the level of PLGF increased. The diastolic blood pressure, systolic blood pressure, and levels of HSP70, PTX3, ET-1, and NO in the combined group are lower than those in the single drug group, and the level of PLGF is higher than that in the single drug group (P < 0.05). During the treatment period, the adverse reaction rate of the combined group is 6.25% compared with 8.33% of the single agent group, and the difference is not statistically significant (P > 0.05). Follow-up visits found that the cesarean section rate and abnormal fetal heart rate in the combined group are 16.67% and 4.17%, respectively, which are lower than 35.42% and 16.67% in the single drug group, and the difference is statistically significant (P < 0.05). Compared with 14.58%, 12.50%, and 2.08% in the single drug group, the neonatal asphyxia rate, premature birth rate, and stillbirth rate in the combined group are 6.25%, 4.17%, and 0.00%, respectively, and the difference is not statistically significant (P > 0.05). Nimodipine combined with magnesium sulfate can effectively control blood pressure in patients with pregnancy-induced hypertension, reduce vascular endothelial damage, regulate the expression of HSP70, PTX3, and PLGF, and improve pregnancy outcomes without increasing adverse reactions.

Regional brain network and behavioral alterations in EGR3 gene transfected rat model of schizophrenia.

Schizophrenia is a severe psychiatric disease while its etiology and effective treatment are not completely clear. A rat model of schizophrenia was previously established by transfecting EGR3 gene into the hippocampus of rats. This study aimed to investigate the behavioral and cerebral alterations of the schizophrenic model rats and the risperidone effects. Twenty-six rats were divided into 3 groups: schizophrenia model group (E group), risperidone treatment group (T group), and healthy control group (H group). Morris water maze and open field test were used as behavioral tests, resting-state functional magnetic resonance imaging (fMRI) was performed after EGR3 gene transfection and risperidone therapy. Graph analyses were used for examining cerebral alterations of the rats. Behavioral tests demonstrated reduced spatial working memory and exploring unfamiliar space ability in schizophrenic model rats. Graph analyses revealed reduced regional architectures in the olfactory bulb, nucleus accumbens, and pineal gland in group E compared to group H (p < 0.05), while group T showed increased regional architecture in pineal gland compared to group E (p < 0.05). Besides, the regional architectures in the olfactory bulb, nucleus accumbens were lower in group T than group H, while the hippocampus showed increased regional architecture in group T compared to group H (p < 0.05). Schizophrenia induced several regional alterations in the cerebrum while risperidone can reverse part of these alterations. This study lends support for future research on the pathology of schizophrenia and provides new insights on the role of risperidone in schizophrenia.

Influence of EGR3 Transfection on Imaging and Behavior in Rats and Therapeutic Effect of Risperidone in Schizophrenia Model.

Schizophrenia is a type of neurodevelopmental psychiatric disorder. However, to date, scientists have not discovered the etiology and effective treatment of this condition. We injected the early growth response gene (EGR3) into the bilateral hippocampus to build a schizophrenia rat model. Behavioral phenotyping and resting-state functional magnetic resonance imaging (rs-fMRI) were used to analyze the behavioral and cerebral alterations in the schizophrenia rat model. The efficacy of risperidone therapy was also evaluated. We divided 34 rats into four groups: schizophrenia model group (E group), sham-operation group (FE group), healthy control group (H group), and risperidone therapy group (T group). Open field test and Morris water maze were conducted as behavioral experiments. Next, we performed rs-fMRI after four weeks of EGR3 transfection and risperidone treatment and analyzed imaging data using regional homogeneity (ReHo), the amplitude of low-frequency fluctuations (ALFF), and functional connectivity (FC). We examined the difference in behavioral and neural activation among the four groups and considered the correlations between behavior and imaging results. EGR3 gene transfection decreased the total moved distance in the open field test and the duration in the Q5 zone of the Morris water maze. Risperidone treatment reversed the trend and improved the performance of rats in these behavioral tests. Schizophrenia induced several neural alterations in ALFF and ReHo metrics of the rat brain, and risperidone could partly reverse these alterations. The results suggest that similar research is required for schizophrenia and that risperidone may be a novel treatment for dysregulated neural activation in schizophrenia.

Overexpression of RASAL1 Indicates Poor Prognosis and Promotes Invasion of Ovarian Cancer.

RAS protein activator like-1 (RASAL1) exists in numerous human tissues and has been commonly demonstrated to act as a tumor suppressor in several cancers. This study aimed to identify the functional characteristics of RASAL1 in ovarian adenocarcinoma and a potential mechanism of action. We analyzed RASAL1 gene expression in ovarian adenocarcinoma samples and normal samples gained from the GEO and Oncomine databases respectively. Then the relationship between RASAL1 expression and overall survival (OS) was assessed using the Kaplan-Meier method. Furthermore, the biological effect of RASAL1 in ovarian adenocarcinoma cell lines was assessed by Quantitative real time-PCR (qRT-PCR), Cell Counting Kit-8 (CCK-8), western blot, wound healing and transwell assay. The statistical analysis showed patients with higher RASAL1 expression correlated with worse OS. The in vitro assays suggested knockdown of RASAL1 could inhibit cell proliferation, cell invasion and migration of ovarian adenocarcinoma. Moreover, the key proteins in the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) signaling pathway were also decreased in ovarian adenocarcinoma cells with RASAL1 silencing. These findings provide promising evidence that RASAL1 may be not only a powerful biomarker but also an effective therapeutic target of ovarian adenocarcinoma.

Increased Iron Deposition on Brain Quantitative Susceptibility Mapping Correlates with Decreased Cognitive Function in Alzheimer's Disease.

The excessive accumulation of iron in deep gray structures is an important pathological characteristic in patients with Alzheimer's disease (AD). Quantitative susceptibility mapping (QSM) is more specific than other imaging-based iron measurement modalities and allows noninvasive assessment of tissue magnetic susceptibility, which has been shown to correlate well with brain iron levels. This study aimed to investigate the correlations between the magnetic susceptibility values of deep gray matter nuclei and the cognitive functions assessed by mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) in patients with mild and moderate AD. Thirty subjects with mild and moderate AD and 30 age- and sex-matched healthy controls were scanned with a 3.0 T magnetic resonance imaging (MRI) scanner. The magnetic susceptibilities of the regions of interest (ROIs), including caudate nucleus (Cd), putamen (Pt), globus pallidus (Gp), thalamus (Th), red nucleus (Rn), substantia nigra (Sn), and dentate nucleus (Dn), were quantified by QSM. We found that the susceptibility values of the bilateral Cd and Pt were significantly higher in AD patients than the controls ( P < 0.05). In contrast, bilateral Rn had significantly lower susceptibility values in AD than the controls. Regardless of gender and age, the increase of magnetic susceptibility in the left Cd was significantly correlated with the decrease of MMSE scores and MoCA scores ( P < 0.05). Our study indicated that magnetic susceptibility value of left Cd could be potentially used as a biomarker of disease severity in mild and moderate AD.

Humanin rescues cultured rat cortical neurons from NMDA-induced toxicity through the alleviation of mitochondrial dysfunction.

N-methyl-D-aspartate (NDMA) receptor-mediated excitotoxicity has been implicated in a variety of pathological situations such as Alzheimer's disease (AD) and Parkinson's disease. However, no effective treatments for the same have been developed so far. Humanin (HN) is a 24-amino acid peptide originally cloned from the brain of patients with AD and it prevents stress-induced cell death in many cells/tissues. In our previous study, HN was found to effectively rescue rat cortical neurons. It is still not clear whether HN protects the neurons through the attenuation of mitochondrial dysfunction. In this study, excitatory toxicity was induced by NMDA, which binds the NMDA receptor in primarily cultured rat cortical neurons. We found that NMDA (100 µmol/L) dramatically induced the decrease of cell viability and caused mitochondrial dysfunction. Pretreatment of the neurons with HN (1 µmol/L) led to significant increases of mitochondrial succinate dehydrogenase (SDH) activity and membrane potential. In addition, HN pretreatment significantly reduced the excessive production of both reactive oxygen species (ROS) and nitric oxide (NO). Thus, HN could attenuate the excitotoxicity caused by the overactivation of the NMDA receptor through the alleviation of mitochondrial dysfunction.

[Recent progress in neuroprotection of humanin against Alzheimer's disease-relevant neurotoxicity].

Alzheimer's disease (AD) is the leading cause of dementia for aging people, and far from control due to its obscure mechanism. Humanin, a 24-aa peptide encoded by a newly identified gene cloned from an apparently normal region of AD brain, can specifically attenuate AD-related neurotoxicity. It protects neurons from insults of various AD genes, anti-APP antibodies and Abeta by forming a homodimer outside and interfering directly or indirectly with the activity of Abeta. Humanin seems, however, not to inhibit other toxic insults to neurons, such as Fas or etoposide, an agent against carcinomatous cells in clinical therapy. So Humanin rescues neurons from various AD-related toxicity specifically with efficiency.