Use of a semi-physiological pharmacokinetic model to investigate the influence of itraconazole on tacrolimus absorption,distribution and metabolism in mice

1.?The aim of this study was to investigate the influence of itraconazole (ITCZ) on tacrolimus absorption, distribution and metabolism by developing a semi-physiological pharmacokinetic model of tacrolimus in mice.

2.?Mice were randomly divided into four groups, namely control group (CG, taking 3?mg kg^?1 tacrolimus only), low-dose group (LDG, taking tacrolimus with 12.5?mg kg^?1 ITCZ), medium-dose group (MDG, taking tacrolimus with 25?mg kg^?1 ITCZ) and high-dose group (HDG, taking tacrolimus with 50?mg kg^?1 ITCZ).

3.?Liver clearance (CL_li) decreased significantly (**p?<?0.01) in LDG (35.3%), MDG (45.2%) and HDG (58.7%) mice compared to CG mice. With respect to gut clearance (CL_gu), significant (**p?<?0.01) decrease was also revealed in LDG (35.9%), MDG (50.2%) and HDG (64.6%) mice. A significant (**p?<?0.01) higher tacrolimus brain-to-blood partition coefficient (K_t,br) was found in MDG (25.3%) and HDG (55.9%) mice than in CG mice. Moreover, a significant (*p?<?0.05) increase (16.3%) was found in the absorption rate constant (K_a) in HDG mice compared to CG mice. There was a significant (**p?<?0.01) association between ITCZ dose and the change in CL_gu (ΔCL_gu, r=??0.790), the change in CL_li (ΔCL_li, r=??0.787) and the change in K_t,br (ΔK_t,br, r?=?0.727), while the association between ITCZ dose and the change in K_a (ΔK_a) was not significant (p?>?0.05).

4.?These findings could be useful in predicting the efficacy and toxicity of tacrolimus, and drug–drug interaction of ITCZ and tarcolimus in human.     

Sex-specific effects of ketogenic diet after pre-exposure to a high-fat,high-sugar diet in rats

Background and aimsThe objectives were to evaluate the relationship between ketogenic diets, the ketone body beta-hydroxybutyrate (BHB), parameters known to increase risk for cardiovascular and metabolic diseases in both sexes, using a pre-clinical model of obesity.Methods and resultsRats had access to a diet high in fat and sugar (HFS) for 12 weeks. After HFS, they switched to chow (HFS–CH) or ketogenic diet (HFS-KD) for 3 weeks to model a dietary intervention. Body weight, adiposity, and food intake were measured. Glucose tolerance and corticosterone response to stress were measured after HFS, then again after the intervention. Both sexes increased body weight, food intake, and adiposity compared to control (CTL) while on HFS. HFS females showed impaired glucose tolerance. HFS males developed a dampened corticosterone to stress, whereas HFS females developed an exacerbated response. The effects of HFS on adiposity and corticosterone were reversed in HFS–CH males. These same improvements were observed in HFS–CH females, although they still had impaired glucose tolerance. HFS-KD males showed some improvements, however, they still had higher body weight and adiposity than CTL. The same pattern was observed in females. These beneficial effects of KD correlated with plasma BHB levels in females but not in males.ConclusionsThese data model effects reported in clinical literature and serve as a valuable translational tool to further test causal mechanisms that lead to desirable outcomes of KD. These sex-specific relationships are important, as KD could potentially affect endocrine mechanisms differently in males and females.     

Altered DNA methylation of glucose transporter 1 and glucose transporter 4 in patients with major depressive disorder

Alterations in brain glucose metabolism and in peripheral glucose metabolism have frequently been observed in major depressive disorder (MDD). The insulin independent glucose transporter 1 (GLUT1) plays a key role in brain metabolism while the insulin-dependent GLUT4 is the major glucose transporter for skeletal and cardiac muscle. We therefore examined methylation of GLUT1 and GLUT4 in fifty-two depressed inpatients and compared data to eighteen healthy comparison subjects. DNA methylation of the core promoter regions of GLUT1 and GLUT4 was assessed by bisulfite sequencing. Further factors determined were fasting glucose, cortisol, insulin, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). We found significantly increased methylation of the GLUT1 in depressed inpatients compared to healthy comparison subjects (CG). Further findings comprise increased concentrations of fasting cortisol, glucose, insulin, and increased IL-6 and TNF-α. After six weeks of inpatient treatment, significantly lower GLUT1 methylation was observed in remitted patients compared to non-remitters. GLUT4 methylation was not different between depressed patients and CG, and did not differ between remitted and non-remitted patients. Although preliminary we conclude from our results that the acute phase of major depressive disorder is associated with increased GLUT1 methylation and mild insulin resistance. The successful treatment of depression is associated with normalization of GLUT1 methylation in remitters, indicating that this condition may be reversible. Failure of normalization of GLUT1 methylation in non-remitters may point to a possible role of impeded brain glucose metabolism in the maintenance of MDD.     

Characterization of pancreatic islet cell tumors and renal tumors induced by a combined treatment of streptozotocin and nicotinamide in male SD rats

We herein investigated the histopathological features, including proliferative activity and immunoexpression, of pancreatic islet cell tumors (ICTs) in male SD rats induced by streptozotocin (STZ) and nicotinamide (NA), and discussed their relevance to biological behaviors and prognoses. A total of 70 and 43% of rats developed ICTs 37–45 weeks after the treatment with STZ (50 or 75 mg/kg, i.v.) and NA (350 mg/kg, twice, p.o.), respectively. Among the islet tumors observed in the STZ/NA-treated groups, 75% were adenomas, while 25% were carcinomas. Most STZ/NA-induced carcinomas were characterized by well-differentiated tumor cells with/without local invasion into the surrounding tissues, and weak proliferative activity. No outcome such as distance metastasis and death was noted. All of the ICTs strongly expressed insulin, part of which had hormone productivity; however there were no hypoglycemia-related clinical signs such as convulsion in these rats 36 weeks after the treatment. These results suggested that rat ICTs induced STZ/NA have small impact on biological activity or prognosis. STZ/NA treatment significantly increased of focal proliferative lesions in the kidney, liver and adrenal glands other than pancreatic islets. Of the STZ/NA-induced kidney tumors, more than 60% were renal cell adenomas, and many of them were basophilic type. The incidence of eosinophilic or clear cell type of tumors was less than 10%, respectively. Immunohistochemical analyses revealed that many of the STZ/NA-induced basophilic type of renal tumors were derived from proximal tubules, whereas the clear cell and eosinophilic types were derived from collecting tubules.     

Performance of blood glucose meters in compliance with current and future clinical ISO15197 accuracy criteria

Since 2003, blood glucose meters for patient self testing are approved in Europe based on the accuracy performance criteria as defined by the ISO15197 guideline. A new draft ISO guideline is currently under regulatory review, which suggests more strict accuracy acceptance criteria, and which may not be entirely fulfilled by currently commercialized blood glucose meter systems. In order to investigate the compliance of BG*Star and iBG*Star and several other blood glucose meters with the new draft ISO guideline, we performed a post-hoc analysis of data obtained from a recently performed ISO-conforming clinical accuracy performance study. This study was performed with 106 patients, clinically presenting with blood glucose levels distributed over the entire measurement range and in line with the glucose distribution requirements as demanded by the guideline. The YSI 2300 STAT Plus analyzer (glucose oxidase) served as reference method.

While all tested meters had been in a high degree of compliance with the current ISO criteria, performance was lower when analyzed in accordance with the new acceptance criteria (95% of readings have to be within ±15?mg/dL for values <100?mg/dL, and within ±15% for values ≥100?mg/dL). The following meters met the new criteria: Accu-Chek Aviva (95.5%/98.6%), BG*Star (98.5%/97.3%), iBG*Star (98.5%/97.3%), FreeStyle Freedom Lite (95.5%/96.6%), and OneTouch Ultra2 (95.5%/96.5%). One meter failed with low blood glucose values (Contour: 90.9%/95.9%).

In conclusion, BG*Star and iBG*Star and several other branded meters met the new draft ISO15197 acceptance criteria, when tested in accordance with the instructions for use and with the ISO accuracy testing protocol in a clinical setting.     

高渗葡萄糖联合胰岛素局部换药治疗咽瘘的临床研究

目的观察高渗葡萄糖联合胰岛素局部换药治疗咽瘘的临床效果，探讨咽瘘的治疗经验。方法回顾性分析12例全喉切除术后并发咽瘘者应用高渗葡萄糖联合胰岛素治疗的临床资料。12例均于常规清创处理后，以50％葡萄糖注射液10～20ml加精蛋白锌胰岛素10～20U的混合液擦洗伤口2或3次，再使用混合液纱条填寒瘘腔，外覆无菌干纱布，最后对咽瘘周围组织适度加压包扎，并观察创面愈合情况和时间。结果12例创面全部达到痊愈标准，平均痊愈时间19．6d；观察6个月，无一例出现吞咽困难。结论高渗葡萄糖联合胰岛素可通过控制创面感染、清除坏死组织、促进肉芽组织和上皮细胞生长等促进全喉切除术后咽瘘创面愈合，方法简单，值得推广应用。     

基于信息化血糖监测系统建立血糖基准报告研究

背景　随着糖尿病患病率的增高，住院患者血糖管理已成为医院关注的焦点，但目前尚缺乏公认的绩效指标定义、指标测算和标准化血糖基准报告，影响了医院血糖管理持续质量改进。目的　基于信息化血糖监测系统（IGMS）构建血糖基准报告，一为同行建立标准化血糖报告提供方法学指导，二为同行提供血糖基准参考。方法　纳入2019年10月至2020年3月遂宁市中心医院安装了IGMS（该系统能自动上传血糖数据和按需求查阅血糖数据）的非重症监护病区（10个内科和7个外科）的糖尿病患者或高血糖患者（无糖尿病病史但随机末梢血糖超过11.1 mmol/L），排除住院第1天的血糖数据。采用群体（population）、患者（patient）和患者日（patient-day）三种模型报告理想血糖、高血糖和低血糖发生率，低血糖报告增加患者低血糖发生天数比、发生频次比和管理及时性比，采用四分位数分析不同病区的血糖数据，并与美国、澳大利亚、重庆和广东医疗机构的血糖数据进行比较。结果　三种模型平均血糖、理想血糖、平均高血糖和任意高血糖（>10.0 mmol/L、≥15.0 mmol/L、≥16.7 mmol/L）、任意低血糖（≤3.9 mmol/L、<3.0 mmol/L、<2.8 mmol/L、<2.2 mmol/L）比较，差异均有统计学意义（P<0.001）。17个病区任意低血糖≤3.9 mmol/L发生>3次者312例（3.9%），发生>3 d者202例（2.5%），复测血糖时间≤15 min者446例（5.6%），>30 min者2 187例（27.5%）。患者日任意高血糖≥15.0 mmol/L、任意低血糖≤3.9 mmol/L、理想血糖下四分位数分别为38.6%、5.5%和38.0%，上四分位数分别为21.5%、2.1%和58.1%。17个病区与美国、澳大利亚、重庆医疗机构的平均高血糖和任意高血糖（>10.0 mmol/L、≥15.0 mmol/L、≥16.7 mmol/L）、任意低血糖（≤3.9 mmol/L、<3.0 mmol/L、<2.8 mmol/L、<2.2 mmol/L）比较，差异均有统计学意义（P<0.05）。本研究内分泌病区和广东省某内分泌病区血糖、理想血糖、任意高血糖≥16.7 mmol/L、任意低血糖≤3.9 mmol/L比较，差异均有统计学意义（P<0.05）。结论　IGMS允许医疗机构建立全方位、标准化血糖报告。因目的不同，其选择模型也不同。群体模型更适用药物管理和风险管理人员，患者模型更适用个体化护理评估，患者日模型适用于某单元或单位进行质量改进方向和目标的制定。     

Measurement of pulse oximetry,capnography and pH

The measurement of arterial oxygen saturations, end-tidal carbon dioxide and pH are all key to modern anaesthetic practice. They can all be measured in a variety of ways, but the most common are discussed in this article. The understanding of the underlying physical principles and how the anaesthetist monitors function to measure these variables is discussed in this article, including limitations and inaccuracies of each technique.