Regulation of cytochrome P450 gene expression by ketamine: a review

Introduction: Although used as an anesthetic drug for decades, ketamine appears to have garnered renewed interest due to its potential therapeutic uses in pain therapy, neurology, and psychiatry. Ketamine undergoes extensive oxidative metabolism by cytochrome P450 (CYP) enzymes. Considerable efforts have been expended to elucidate the ketamine-induced regulation of CYP gene expression. The safety profile of chronic ketamine administration is still unclear. Understanding how ketamine regulates CYP gene expression is clinically meaningful.

Areas covered: In this article, the authors provide a brief review of clinical applications of ketamine and its metabolism by CYP enzymes. We discuss the effects of ketamine on the regulation of CYP gene expression, exploring aspects of cytoskeletal remodeling, mitochondrial functions, and calcium homeostasis.

Expert opinion: Ketamine may inhibit CYP gene expression through inhibiting calcium signaling, decreasing ATP levels, producing excessive reactive oxygen species, and subsequently perturbing cytoskeletal dynamics. Further research is still needed to avoid possible ketamine–drug interactions during long-term use in the clinic.     

Functional Mixed Effects Model for the Analysis of Dose-Titration Studies

Functional data analysis, which analyzes data that can be represented by curves or images, has many potential applications in clinical trials. Motivated by a real example, this study constructs a functional mixed effects model for analyzing a clinical outcome that is observed continuously over a long period of time. A penalized spline (P-spline)-based method is applied to obtain the estimators of the mean function and the time-varying coefficients. Simulation studies are conducted to investigate the consistency, efficiency, and robustness of the method. To illustrate the use of the method, a real data analysis is performed and produces interpretable results.     

Population pharmacokinetics of theophylline in adult Chinese patients with asthma and chronic obstructive pulmonary disease

Background Theophylline has a narrow therapeutic range and large interindividual variability in blood levels, so a thorough understanding of its pharmacokinetic characteristics is essential. Population pharmacokinetic (PPK) approaches could achieve it and many PPK studies of theophylline have been reported in infants. However, none was conducted in Chinese adults and none has explored the effect of CYP1A2 genotypes on the PPK characteristics of theophylline in adults. Objective To evaluate the PPK characteristics of theophylline and to assess the possible influence of covariates, including CYP1A2 genotypes, on theophylline clearance in Chinese adult patients. Setting The study is conducted at the department of respiration in Zhujiang Hospital, Guangzhou, China. Methods Theophylline concentrations were obtained from eligible patients and were measured by high performance liquid chromatography. The polymorphisms of ??3860G?>?A, ??163C?>?A, C5347T (CYP1A2*1B) and G-3113A were genotyped using a direct sequencing method. Then, CYP1A2 genotypes, age, fat-free mass (FFM) and other covariates were used to develop a PPK model by NONMEM software. Bootstrap analysis was used to asses the accuracy and prediction of the PPK model. Main outcome measure The concentration and clearance of theophylline. Results A total of 134 theophylline concentrations from 95 patients were obtained. The final model was as follows: CL/F(L/h)?=?4.530?×?(FFM/56.1)^0.75 ×?0.713^CYP1A2*1B, the inter-individual variability in clearance/bioavailability (CL/F) was 44.0%, and the residual variability was 9.8%. The final model was proved to be reliable by bootstrap analysis. Conclusion Theophylline clearance was significantly associated with FFM and CYP1A2*1B genotypes in Chinese adult patients.     

中医辨证治疗高血压的效果分析

目的:分析中医辨证治疗高血压的效果.方法:随机抽取2015年3月～2016年9月128例高血压患者,分为对照组(n=64)与观察组(n=64),对照组予以西医的治疗方法,即服用常规的降血压药物;观察组予以中医辨证治疗的方法,即依据不同的症状服用不同的中药药剂,观察两组临床效果、治疗后的血压与不良反应.结果:观察组临床有效率为89.06％,明显高于对照组的70.31％(P<0.05);同时两组血压变化明显,并且两组均未出现不良反应.结论:采取中医辨证治疗高血压,可获得良好的治疗效果,提升康复率,值得临床推广.     

Peripheral blood leukocyte telomere length is associated with age but not renal function: A cross-sectional follow-up study

Objectives

We aimed to evaluate the relationship between baseline renal function and changes in telomere length in Han Chinese.

Methods

The telomere restriction fragment (TRF) length of leukocytes in the peripheral blood was measured in healthy volunteers recruited in 2014. The estimated glomerular filtration rate (eGFR) was calculated based on serum creatinine (Scr) and serum cystatin C (CysC)-eGFRcys and eGFRScr-cys through the Cockcroft-Gault formula (eGFRC-G) or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI / eGFRCKD-EPI) equation. The correlation between telomere length changes over time and renal function was analyzed.

Results

Leukocyte TRF lengths were negatively correlated to age (r = -0.393, p < 0.001) and serum CysC (r = -0.180, p < 0.01), while positively associated with eGFRCKD-EPI, eGFRC-G, eGFRcys, and eGFRScr-cys (r = 0.182, 0.122, 0.290, and 0.254 respectively, p < 0.01). The 3-year change of telomere length was 46 bp/years. When adjusted for age, the associations between telomere length changes and baseline, subsequent TRF lengths, and serum CysC were no longer present. No association was observed between TRF length changes and renal function.

Conclusion

The rate of telomere length changes was affected by age and baseline telomere length. The telomere length changes might be important markers for aging.

     

Childhood polybrominated diphenyl ether (PBDE) exposure and executive function in children in the HOME Study

Prenatal exposure to polybrominated diphenyl ethers (PBDEs) have been reported to impair executive function in children, but little is known whether childhood PBDE exposures play a role. Using the Health Outcomes and Measures of the Environment (HOME) Study, a prospective birth cohort in the greater Cincinnati area, we investigated the association between repeated measures of PBDEs during childhood and executive function at 8 years in 208 children and whether effect modification by child sex was present. We used child serum collected at 1, 2, 3, 5, and 8 years to measure PBDEs. The Behavior Rating Inventory of Executive Function was completed by parents to assess executive function at 8 years. We used multiple informant models to examine childhood PBDEs during several exposure windows. Null associations were observed between early childhood PBDEs and executive function. However, we observed significant adverse associations between a 10-fold increase in concurrent concentrations of BDE-28 (β = 4.6, 95% CI 0.5, 8.7) and BDE-153 (β = 4.8, 95% CI 0.8, 8.8) with behavioral regulation. In addition, PBDEs at 8 years were significantly associated with poorer emotional and impulse control. No associations were noted between childhood PBDEs and metacognition or global executive function. However, child sex significantly modified the associations, with significantly poorer executive function among males with higher concurrent BDE-153, and null associations in females. Our study findings suggest that concurrent PBDE exposures during childhood may be associated with poorer executive function, specifically behavior regulation. Males may also be more sensitive to adverse associations of concurrent PBDEs on executive function.     

Parent–child separation: the relationship between separation and psychological adjustment among Chinese rural children

Purpose

The current study aimed to explore the characteristics of psychological adjustment among Chinese left-behind children (LBC) in rural areas, and to examine the association between separation duration from parent/parents (SDP) and children’s psychological adjustment and the extent to which personality mediates this hypothesized link.

Methods

We surveyed 534 rural children and adolescents aged 10–17 years at school (440 LBC and 94 non-LBC) in 2013, who were selected for participation using stratified cluster sampling from two counties in Chongqing, China. Measures used included socio-demographic variables, age at the commencement and end of the separation from parents, the revised Chinese Juvenile Eysenck Personality Questionnaire, and the Adolescent Psychological Adaptability Scale.

Results

Most children (82.4%) had experienced separation from parents. t test results showed a marginally significant difference (p?=?.08) in psychological adjustment between LBC (mean?=?64.44, SD?=?8.62) and non-LBC (mean?=?66.16, SD?=?9.26). LBC’s mean SDP was 5.64 years (SD?=?3.90). Correlation analysis showed that children’s SDP was negatively associated with psychological adjustment. Structural equation modeling showed that neuroticism, but not extraversion or psychoticism, fully mediated the link between children’s SDP and psychological adjustment.

Conclusion

Personality (neuroticism) is one of the mediating pathways through which long-term SDP may predict poor psychological adjustment among children. Given the detrimental impact of long-term SDP, interventions should target the mediating pathway to buffer against the negative impact of parental separation on the affected rural children and to improve their mental health.

     

Effects of systemic fluoride and in vitro fluoride treatment on enamel crystals

Systemically administered fluoride at a concentration of 75 ppm increases the surface roughness of developing enamel crystals in rats, which may be significant in advancing our understanding of the biological mechanism of fluorosis. Thus, the aim of this study was to investigate whether the increased surface roughness may be a result of surface restructuring by the direct action of fluoride at the crystal surface. We examined the fluoride dose-dependent roughening of enamel crystal surfaces in vivo, in the rat, and whether this roughening could be mimicked by the in vitro treatment of rat enamel crystals with neutral pH fluoride solutions. Our results showed that enamel crystal surface roughness increased after treatment with increasing fluoride ion concentrations, whether applied in vitro or administered systemically. This suggests a mechanism, alongside others, for the increased surface roughness of crystals in fluorotic enamel.