Pharmacokinetic study of small molecule inhibitor SYHA1809 in Beagle dogs / 中国药房

OBJECTIVE To study the pharmacokinetics of small molecule inhibitor SYHA1809 in Beagle dogs. METHODS LC-MS/MS method was adopted. Beagle dogs were randomly divided into single intravenous administration group （3.75 mg/kg）， single low-dose intragastric administration group （3.75 mg/kg）， single medium-dose intragastric administration group （7.5 mg/kg）， single high-dose intragastric administration group （15 mg/kg） and multiple intragastric administration group （7.5 mg/kg， once a day， for 7 consecutive days）， with 6 dogs in each group， half male and half female. The plasma samples of Beagle dogs were collected in each group according to the set time point， and underwent LC-MS/MS quantitative analysis after preprocessing. The pharmacokinetic parameters were calculated by using Phoenix WinNonlin 8.0 software using obtained data. RESULTS After intravenous injection， CL of SYHA1809 in Beagle dogs was （2.70±0.48） mL/（min·kg）， steady-state distribution volume was 0.757 L/kg， and t1/2 was （3.35±1.36） h； after single intragastric administration of low-dose， medium-dose and high-dose of SYHA1809， average tmax was （0.53±0.02） h， and the blood drug concentration increased with the increase of dose； after single intragastric administration of 3.75 mg/kg SYHA1809， the absolute bioavailability was 83.5%； within the dose range of 3.75-15 mg/kg， the increase in cmax and AUC of SYHA1809 was positively correlated with the dose； after intragastric administration of 7.5 mg/kg SYHA1809 for 7 consecutive days， the pharmacokinetic parameters of SYHA1809 were comparable to those of a single intragastric administration of the same dose， with no statistically significant difference （P＞0.05）. CONCLUSIONS SYHA1809 is absorbed rapidly in Beagle dogs， shows the dose-dependent blood concentration， high bioavailability， no obvious accumulation after multiple intragastric administration， and good pharmacokinetic behavior.

Preclinical and early clinical studies of a novel compound SYHA1813 that efficiently crosses the blood-brain barrier and exhibits potent activity against glioblastoma

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults and is poorly controlled. Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression, and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment. Therefore, this study developed a novel and selective inhibitor of CSF1R and VEGFR, SYHA1813, possessing potent antitumor activity against GBM. SYHA1813 inhibited VEGFR and CSF1R kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo. SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models, including temozolomide (TMZ) insensitive tumors. Notably, SYHA1813 could penetrate the blood-brain barrier (BBB) and prolong the survival time of mice bearing intracranial GBM xenografts. Moreover, SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody. As a clinical proof of concept, SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial. The data of this study support the rationale for an ongoing phase I clinical study (ChiCTR2100045380).

Hepatic retinaldehyde deficiency is involved in diabetes deterioration by enhancing PCK1- and G6PC-mediated gluconeogenesis

Type 2 diabetes (T2D) is often accompanied with an induction of retinaldehyde dehydrogenase 1 (RALDH1 or ALDH1A1) expression and a consequent decrease in hepatic retinaldehyde (Rald) levels. However, the role of hepatic Rald deficiency in T2D progression remains unclear. In this study, we demonstrated that reversing T2D-mediated hepatic Rald deficiency by Rald or citral treatments, or liver-specific Raldh1 silencing substantially lowered fasting glycemia levels, inhibited hepatic glucogenesis, and downregulated phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6-phosphatase (G6PC) expression in diabetic db/db mice. Fasting glycemia and Pck1/G6pc mRNA expression levels were strongly negatively correlated with hepatic Rald levels, indicating the involvement of hepatic Rald depletion in T2D deterioration. A similar result that liver-specific Raldh1 silencing improved glucose metabolism was also observed in high-fat diet-fed mice. In primary human hepatocytes and oleic acid-treated HepG2 cells, Rald or Rald + RALDH1 silencing resulted in decreased glucose production and downregulated PCK1/G6PC mRNA and protein expression. Mechanistically, Rald downregulated direct repeat 1-mediated PCK1 and G6PC expression by antagonizing retinoid X receptor α, as confirmed by luciferase reporter assays and molecular docking. These results highlight the link between hepatic Rald deficiency, glucose dyshomeostasis, and the progression of T2D, whilst also suggesting RALDH1 as a potential therapeutic target for T2D.

Exploratory study of tracheal extubation in operating room after single-lung transplantation / 器官移植

Objective To evaluate the feasibility and safety of tracheal extubation in operating room for patients with end-stage chronic obstructive pulmonary disease (COPD) after single-lung transplantation. Methods Clinical data of 57 recipients who underwent single-lung transplantation due to end-stage COPD were retrospectively analyzed. According to the evaluation indexes of tracheal extubation in operating room established by our hospital, 17 recipients eligible for tracheal extubation in operating room were assigned into the operating room extubation group (OR extubation group) and 40 recipients receiving tracheal extubation in intensive care unit (ICU) were allocated in the ICU extubation group. The evaluation results of intraoperative tracheal extubation and postoperative recovery were compared between two groups. Results Compared with the ICU extubation group, recipients in the OR extubation group had higher oxygenation index, lower arterial partial pressure of carbon dioxide (PaCO2), lower blood lactic acid level, less fluctuation range of blood pressure and fewer cases receiving extracorporeal membrane oxygenation (ECMO) during operation (all P < 0.05). Two recipients in the OR extubation group received repeated tracheal intubation at 6 and 8 h after returning to ICU, and tracheal extubation at postoperative 6 and 9 d. In the OR extubation group, time of postoperative mechanical ventilation, length of postoperative ICU and hospital stay of the recipients were shorter than those in the ICU extubation group (all P < 0.05). The incidence of grade 3 primary graft dysfunction (PGD), atrial tachyarrhythmia, continuous renal replacement therapy and 1-year survival rate did not significantly differ between two groups (all P > 0.05). Conclusions The tracheal extubation regimen in the operating room for COPD patients after single-lung transplantation established by our hospital is safe and feasible, which shortens the time of postoperative mechanical ventilation, the length of postoperative ICU and hospital stay, whereas does not increase the incidence of postoperative complications.

PXR activation impairs hepatic glucose metabolism partly via inhibiting the HNF4α-GLUT2 pathway

Drug-induced hyperglycemia/diabetes is a global issue. Some drugs induce hyperglycemia by activating the pregnane X receptor (PXR), but the mechanism is unclear. Here, we report that PXR activation induces hyperglycemia by impairing hepatic glucose metabolism due to inhibition of the hepatocyte nuclear factor 4-alpha (HNF4α)‒glucose transporter 2 (GLUT2) pathway. The PXR agonists atorvastatin and rifampicin significantly downregulated GLUT2 and HNF4α expression, and impaired glucose uptake and utilization in HepG2 cells. Overexpression of PXR downregulated GLUT2 and HNF4α expression, while silencing PXR upregulated HNF4α and GLUT2 expression. Silencing HNF4α decreased GLUT2 expression, while overexpressing HNF4α increased GLUT2 expression and glucose uptake. Silencing PXR or overexpressing HNF4α reversed the atorvastatin-induced decrease in GLUT2 expression and glucose uptake. In human primary hepatocytes, atorvastatin downregulated GLUT2 and HNF4α mRNA expression, which could be attenuated by silencing PXR. Silencing HNF4α downregulated GLUT2 mRNA expression. These findings were reproduced with mouse primary hepatocytes. Hnf4α plasmid increased Slc2a2 promoter activity. Hnf4α silencing or pregnenolone-16α-carbonitrile (PCN) suppressed the Slc2a2 promoter activity by decreasing HNF4α recruitment to the Slc2a2 promoter. Liver-specific Hnf4α deletion and PCN impaired glucose tolerance and hepatic glucose uptake, and decreased the expression of hepatic HNF4α and GLUT2. In conclusion, PXR activation impaired hepatic glucose metabolism partly by inhibiting the HNF4α‒GLUT2 pathway. These results highlight the molecular mechanisms by which PXR activators induce hyperglycemia/diabetes.

Bioequivalence study of pramipexole hydrochloride tablets in Chinese healthy subjects / 中国临床药理学与治疗学

AIM: To assess the bioequivalence of pramipexole hydrochloride tablets with reference(Sifrol). METHODS: A randomized, open-label, 2-period crossover study was conducted in 48 healthy Chinese volunteers under fasted or fed conditions (24 volunteers for each condition). In each session, the subjects received a single oral dose of 0.25 mg test (T) or reference (R) formulation. Pramipexole concentrations in plasma were determined by a validated HPLC-MS/MS. Pharmacokinetic parameters were calculated using a non-compartmental model through Phoenix WinNonlin version 6.4. Other statistic analysis were analyzed by using software of SAS 9.3. RESULTS: The pharmacokinetic parameters of test drug and reference drug under fasted condition(n=20) were: C

Value of diffusion-weighted imaging in distinguishing pancreatic carcinoma from mass-forming chronic pancreatitis: a meta-analysis / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Several previous studies have shown that diffusion-weighted imaging (DWI) can provide additional information for focal pancreatic lesions by demonstrating more restricted diffusion in solid malignant tumors than in chronic pancreatitis, which can be indicated by a decreased apparent diffusion coefficient (ADC). However, these studies have a modest sample size and convey inconclusive results. The aim of this study was to determine, in a meta-analysis, the diagnostic performance of quantitative diffusion-weighted magnetic resonance imaging in distinguishing pancreatic carcinoma from mass-forming chronic pancreatitis.</p><p><b>METHODS</b>We determined the sensitivities and specificities across studies. A summary receiver operator characteristic (sROC) curve was constructed to calculate the area under the curve (AUC).</p><p><b>RESULTS</b>The pooled sensitivity of DWI was 0.86 (95% CI: 0.80-0.91) and the pooled specificity was 0.82 (95% CI: 0.72-0.89). The AUC of the sROC was 0.91 (95% CI: 0.88-0.93).</p><p><b>CONCLUSIONS</b>DWI may be a potentially technically feasible tool for differentiating pancreatic carcinoma from mass-forming chronic pancreatitis. However, large-scale randomized control trials are necessary to assess its clinical value.</p>

Pharmacodynamics, pharmacokinetics and tissue distribution of liposomal mitoxantrone hydrochloride / 药学学报

This study is to compare the pharmacodynamics, pharmacokinetics and tissue distribution of liposomal mitoxantrone (Mit-lipo) and free mitoxantrone (Mit-free). The antineoplastic effect of Mit-lipo was evaluated on PC-3 human xenograft tumor model after repeated intravenous injection at dose levels of 1, 2 and 4 mg x kg(-1). The pharmacokinetic study of Mit-lipo and Mit-free was performed on dogs following a single intravenous injection. The tissue distribution of Mit-lipo and Mit-free was observed on S-180 bearing mice after a single intravenous injection. (1) Pharmacodynamics: Mit-lipo dose-dependently inhibited PC-3 tumor growth at a dose ranging from 1 to 4 mg x kg(-1). The antitumor effect studies showed that Mit-lipo significantly improved the therapeutic effect in comparison with free drug. (2) Pharmacokinetics: in comparison with Mit-free, the AUC and t(1/2) values of Mit-lipo at the same dose level were higher than those of Mit-free in Beagle dogs. The results showed that Mit-lipo had long circulation characteristics. (3) Tissue distribution in S-180 bearing mice: compared to Mit-free, Mit-lipo preferentially accumulated into tumor zones instead of normal tissues. Tumor AUC in Mit-lipo treated animals was 8.7 fold higher than that in mice treated with the same dose of Mit-free. The Cmax values of Mit-lipo in heart, kidney, lung, spleen and intestinal tissue in Mit-lipo were 30.2%, 161.6%, 20.2%, 27.9% and 78.3% lower than those of Mit-free, respectively. The pharmacokinetics and tissue distribution of Mit-lipo changed obviously, thus increasing therapeutic effect and improving drug therapeutic index.

The reform and practice in teaching anesthetic pharmacology / 中华医学教育探索杂志

Anesthetic pharmacology is a bridge subject that connects preclinical medicine with clinical medicine,and multiple methods of teaching in this subject would play an vital role in training student’s idea of scientific research and creativity.Combining modern teaching means with clinical medicine is an evaluative tendency for education of anesthetic pharmacology in the future.