RESUMO
AIMS: Ketamine analgesia is limited by low intrinsic efficacy compounded by large interindividual variability in drug responses, possibly due to the heterogeneity in drug concentration. The CYP2B6*6 allele is associated with substantially reduced ketamine metabolism in vitro and, therefore, may affect ketamine clearance. Our aims were to examine the impact of the CYP2B6*6 allele on ketamine plasma clearance and on adverse effects in chronic pain patients. METHODS: CYP2B6 genotypes were identified in 49 chronic pain patients who received 24 h continuous subcutaneous infusions of ketamine. Steady-state plasma concentrations of ketamine (Css,k ) and norketamine (Css,nk ) were determined using HPLC. RESULTS: The median plasma clearance of ketamine after 100 mg 24 h(-1) dose was significantly lower in patients with the CYP2B6*6/*6 (21.6 l h(-1) ) and CYP2B6*1/*6 (40.6 l h(-1) ) genotypes compared with patients with the CYP2B6*1/*1 genotype (68.1 l h(-1) , P < 0.001). The ketamine : norketamine plasma metabolic ratio was significantly higher in patients with the CYP2B6*6/*6 genotype than in those with the CYP2B6*1/*6 and the CYP2B6*1/*1 genotypes (P < 0.001). Patients who experienced adverse effects had lower plasma clearance (45.6 l h(-1) ) than those who did not (52.6 l h(-1) , P = 0.04). The CYP2B6*6 genotype and age, and their combined impact explained 40%, 30% and 60% of the variation in Css,k , respectively. Similar results were observed after higher doses. CONCLUSIONS: The CYP2B6*6 allele is associated with a substantial decrease in steady-state ketamine plasma clearance in chronic pain patients. The decreased clearance and resultant higher plasma concentrations may be associated with a higher incidence of ketamine adverse effects.
Assuntos
Analgésicos/efeitos adversos , Analgésicos/farmacocinética , Dor Crônica/tratamento farmacológico , Citocromo P-450 CYP2B6/genética , Ketamina/efeitos adversos , Ketamina/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos/administração & dosagem , Analgésicos/uso terapêutico , Dor Crônica/sangue , Dor Crônica/enzimologia , DNA/genética , Método Duplo-Cego , Feminino , Frequência do Gene , Genótipo , Humanos , Ketamina/administração & dosagem , Ketamina/uso terapêutico , Modelos Lineares , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-IdadeRESUMO
Ketamine is primarily metabolized to norketamine by hepatic CYP2B6 and CYP3A4-mediated N-demethylation. However, the relative contribution from each enzyme remains controversial. The CYP2B6*6 allele is associated with reduced enzyme expression and activity that may lead to interindividual variability in ketamine metabolism. We examined the N-demethylation of individual ketamine enantiomers using human liver microsomes (HLMs) genotyped for the CYP2B6*6 allele, insect cell-expressed recombinant CYP2B6 and CYP3A4 enzymes, and COS-1 cell-expressed recombinant CYP2B6.1 and CYP2B6.6 protein variant. Effects of CYP-selective inhibitors on norketamine formation were also determined in HLMs. The two-enzyme Michaelis-Menten model best fitted the HLM kinetic data. The Michaelis-Menten constants (K(m)) for the high-affinity enzyme and the low-affinity enzyme were similar to those for the expressed CYP2B6 and CYP3A4, respectively. The intrinsic clearance for both ketamine enantiomers by the high-affinity enzyme in HLMs with CYP2B6*1/*1 genotype were at least 2-fold and 6-fold higher, respectively, than those for CYP2B6*1/*6 genotype and CYP2B6*6/*6 genotype. The V(max) and K(m) values for CYP2B6.1 were approximately 160 and 70% of those for CYP2B6.6, respectively. N,N'N'-triethylenethiophosphoramide (thioTEPA) (CYP2B6 inhibitor, 25 µM) and the monoclonal antibody against CYP2B6 but not troleandomycin (CYP3A4 inhibitor, 25 µM) or the monoclonal antibody against CYP3A4 inhibited ketamine N-demethylation at clinically relevant concentrations. The degree of inhibition was significantly reduced in HLMs with the CYP2B6*6 allele (gene-dose P < 0.05). These results indicate a major role of CYP2B6 in ketamine N-demethylation in vitro and a significant impact of the CYP2B6*6 allele on enzyme-ketamine binding and catalytic activity.
Assuntos
Alelos , Hidrocarboneto de Aril Hidroxilases/química , Hidrocarboneto de Aril Hidroxilases/metabolismo , Ketamina/química , Ketamina/metabolismo , Adulto , Idoso , Animais , Células COS , Chlorocebus aethiops , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Metilação de DNA , Feminino , Humanos , Insetos , Masculino , Pessoa de Meia-Idade , EstereoisomerismoRESUMO
BACKGROUND: Reports regarding the ability of the anesthetic drug ketamine to attenuate the inflammatory response to surgery are conflicting. In this systematic review we examined the effect of perioperative ketamine administration on postoperative inflammation as assessed by concentrations of the biomarker interleukin-6 (IL-6). METHODS: This study was based on a systematic search in PubMed, Scopus, Web of Knowledge, and the Cochrane Library. English written randomized controlled trials conducted in humans were eligible. To be included in the analysis, outcome had to relate to inflammation or immune modulation. Each study was reviewed independently by 2 assessors. Data were analyzed according to the GRADE's approach and reported in compliance with the PRISMA recommendations. RESULTS: Fourteen studies were eligible for evaluation (684 patients). Surgery was performed under general anesthesia, and ketamine was given before or during the surgery in varied doses Eight studies involved cardiopulmonary bypass operations, 4 were for abdominal surgery, 1 thoracic surgery, and 1 cataract surgery. Three studies were deemed of low quality. Nine studies measured IL-6 concentrations within the first 6 hours postoperatively; but in 3 studies, other potent anti-inflammatory drugs were used as premedication or during the operation; thus 6 studies (n = 331) were included in the meta-analysis. Using postoperative IL-6 concentrations as an outcome, ketamine had an anti-inflammatory effect; the meta-analysis showed a mean preoperative-postoperative IL-6 concentration difference (95% confidence interval) of -71 (-101 to -41) pg/mL. CONCLUSIONS: It can be concluded that intraoperative administration of ketamine significantly inhibits the early postoperative IL-6 inflammatory response. Future studies should further examine the anti-inflammatory effect of ketamine during major surgery, determine whether ketamine treatment alters functional outcomes, elucidate the mechanisms of its anti-inflammatory effect, and suggest an appropriate dosing regimen.
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Anti-Inflamatórios/administração & dosagem , Cuidados Intraoperatórios/métodos , Ketamina/administração & dosagem , Complicações Pós-Operatórias/prevenção & controle , Humanos , Inflamação/sangue , Inflamação/etiologia , Inflamação/prevenção & controle , Interleucina-6/sangue , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodosRESUMO
The heading and flowering stages are crucial for wheat growth and should be used for fusarium head blight (FHB) and other plant prevention operations. Rapid and accurate monitoring of wheat growth in hilly areas is critical for determining plant protection operations and strategies. Currently, the operation time for FHB prevention and plant protection is primarily determined by manual tour inspection of plant growth, which has the disadvantages of low information gathering and subjectivity. In this study, an unmanned aerial vehicle (UAV) equipped with a multispectral camera was used to collect wheat canopy multispectral images and heading rate information during the heading and flowering stages in order to develop a method for detecting the appropriate time for preventive control of FHB. A 1D convolutional neural network + decision tree model (1D CNN + DT) was designed. All the multispectral information was input into the model for feature extraction and result regression. The regression revealed that the coefficient of determination (R 2) between multispectral information in the wheat canopy and the heading rate was 0.95, and the root mean square error of prediction (RMSE) was 0.24. This result was superior to that obtained by directly inputting multispectral data into neural networks (NN) or by inputting multispectral data into NN via traditional VI calculation, support vector machines regression (SVR), or decision tree (DT). On the basis of FHB prevention and control production guidelines and field research results, a discrimination model for FHB prevention and plant protection operation time was developed. After the output values of the regression model were input into the discrimination model, a 97.50% precision was obtained. The method proposed in this study can efficiently monitor the growth status of wheat during the heading and flowering stages and provide crop growth information for determining the timing and strategy of FHB prevention and plant protection operations.
Assuntos
Redes Neurais de Computação , Triticum , Diagnóstico por Imagem , Máquina de Vetores de SuporteRESUMO
Exercise is considered as a favorable measure to prevent and treat childhood obesity. However, the underlying mechanisms of exercise-induced beneficial effects and the difference between obese and non-obese individuals are largely unclear. Recently, miR-27a is recognized as a central upstream regulator of proliferator-activated receptor γ (PPAR-γ) in contributing to various physiological and pathological processes. This study aims to explore the possible cause of exercise affecting white adipose tissue (WAT) browning and reversing skeletal muscle insulin resistance in obese/non-obese immature bodies. For simulating the process of childhood obesity, juvenile mice were fed with a basal diet or high-fat diet (HFD) and took 1 or 2 h swimming exercise simultaneously for 10 weeks. The obese animal model was induced by the HFD. We found that exercise hindered HFD-induced body fat development in growing mice. Exercise modified glucolipid metabolism parameters differently in the obese/non-obese groups, and the changes of the 2 h exercise mice were not consistent with the 1 h exercise mice. The level of serum exosomal miR-27a in the non-exercise obese group was increased obviously, which was reduced in the exercise obese groups. Results from bioinformatics analysis and dual-luciferase reporter assay showed that miR-27a targeted PPAR-γ. Exercise stimulated WAT browning; however, the response of obese WAT lagged behind normal WAT. In the HFD-fed mice, 2 h exercise activated the IRS-1/Akt/GLUT-4 signaling pathway in the skeletal muscles. In summary, our findings confirmed that exercise-induced beneficial effects are associated with exercise duration, and the response of obese and non-obese bodies is different. Exosomal miR-27a might be a crucial node for the process of exercise-induced browning of WAT and improving skeletal muscle insulin sensitivity.
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Mu opioid receptor (OPRM1) gene variants, particularly the common A118G single nucleotide polymorphism (SNP), are among the most frequently studied candidate genes associated with opioid dependence. However, despite numerous case-control studies and meta-analyses, no definitive conclusion has been reached regarding the association of the A118G SNP and risk of developing opioid dependence. This study aimed to resolve this discrepancy by reinvestigating the association between A118G SNP allelic, and for the first time, genotype frequencies and opioid dependence. A meta-analysis of sixteen case-control studies of opioid dependence was performed with a total of 5169 subjects. No association between the A118G allele (P = 0.23) and genotype (P = 0.34) frequencies and opioid dependence was found. However, significant heterogeneity between studies precluded highly definitive conclusions. In addition, the possibility that other OPRM1 SNPs albeit rarer may influence the risk of opioid dependence remains to be investigated at this level. Nonetheless, despite no evidence of a direct association with risk of dependence, A118G may still influence the pharmacological response to opioids impacting on an individual's dosage requirements.