Consistency of orthodontists' clinical decisions: A systematic review, meta-analysis, and theory development.

INTRODUCTION: The purpose of this systematic review and meta-analysis is to provide a literature-based estimate of the consistency of orthodontists' clinical decisions. METHODS: A systematic review of the literature using a modified Reporting Items for Systematic Reviews and Meta-Analyses approach identified 20 articles, representing 53 unique datasets, reporting kappa statistics and standard errors for situations allowing intrarater or interrater comparison on decisions such as the need for treatment, extraction, surgery, and various specific treatment approaches. Meta-regression based on random effect models was used to explore the shape of the underlying distribution, the prevalence of the target condition in the data set, and the professional experience of raters as covariables. RESULTS: No evidence of publication bias was found. Common patient records accounted for approximately 25% of the variance between orthodontists and 33% of the variance within orthodontists making the same decision from the same records. Random and representative samples were judged more consistently than were samples chosen to contain borderline cases. (P <0.001). Raters were in greater agreement on the presence of target conditions than their absence (P <0.001). Residents were more consistent than were practicing orthodontists or dental students (P <0.006). CONCLUSIONS: Low consistency was found among orthodontists making clinical decisions from common records. Factors associated with samples and raters suggest an underlying pattern of orthodontists viewing cases through personal mental frameworks.

Investigation of the impact of grapefruit juice, pomegranate juice and tomato juice on pharmacokinetics of brexpiprazole in rats using UHPLC-QTOF-MS.

Brexpiprazole (BRX) is approved for the treatment of schizophrenia and major depressive disorders and it is mainly metabolized by CYP3A4 and CYP2D6. Grapefruit juice (GFJ), pomegranate juice (PJ) and tomato juice (TJ) have the potential to inhibit CYP3A4 enzymes in the body. However, fruit juice-drug interactions between BRX and GFJ, PJ and TJ have not been studied extensively. The present study describes the influence of GFJ, PJ and TJ on the pharmacokinetic parameters of BRX in rats. The study samples were analyzed using a mass-accurate and single-step bioanalytical method by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry over a wide calibration range of 20-1,500 ng/ml. The results of the pharmacokinetic study denoted that the combined administration of GFJ and PJ could increase systemic exposure of BRX. The area under the curve of BRX increased 3.43- and 1.88-fold with co-administration of GFJ and PJ, respectively, while TJ with BRX had no effect on the area under the curve. Time to peak concentration and half-life were not significantly changed by any juice co-administration. The results show that GFJ and PJ affect the pharmacokinetic profile of BRX and hence advice needs to be given to patients.

Metabolite profiling of IMID-2, a novel anticancer molecule of piperazine derivative: In silico prediction, in vitro and in vivo metabolite characterization using UPLC-QTOF-MS/MS.

IMID-2, a newly identified piperazine-based anticancer molecule, has been shown to be cytotoxic against various cancer cell lines. The primary aim of this research was to identify and characterize possible metabolites of the molecule formed during biotransformation. A metabolite identification study was first executed using an in silico tool to predict the possible metabolism sites of IMID-2. Thereafter, metabolites generated in vitro (rat liver microsomes, rat S9 fractions and human liver microsomes) and in vivo (rat plasma, urine and feces) were identified and characterized employing UPLC-QTOF-MS/MS. A total of eight metabolites, among which were six in phase I and two in phase II reactions, were recognized. The plausible structure of the metabolites and probable metabolic pathway have been established based on the mass fragmentation pattern, mass ppm error, ring double bond calculation and nitrogen rule. The majority of phase I metabolites were generated by N-oxidation, hydroxylation, oxidative deamination followed by reduction, oxidative dechlorination, N-dearylation, and N-dealkylation. Glucuronidation played a significant role in the formation of phase II metabolites of the molecule.

1-(Benzo[b]thiophen-4-yl)piperazine Ring Induced Bioactivation of Brexpiprazole in Liver Microsomes: Identification and Characterization of Reactive Conjugates Using Ultra-High-Performance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry.

BACKGROUND AND OBJECTIVES: Brexpiprazole is an atypical antipsychotic approved for the treatment of schizophrenia and major depressive disorders in adults. The structure of brexpiprazole contains well-known structural alerts like a thiophene ring, piperazine ring and quinolinone motifs. Additionally, the literature reveals that its structural analog, aripiprazole, could generate reactive intermediates. However, the bioactivation potential of brexpiprazole is yet unknown. Therefore, this study was planned to identify and characterize reactive adducts of brexpiprazole and its metabolites. METHODS: Based on the reactivity, the potential atomic sites for a reactive intermediate generation were predicted by a xenosite web predictor tool for glutathione, cyanide, protein and DNA. To study the metabolic activation of brexpiprazole, the drug was individually incubated for 2 h at 37 °C with pooled male rat liver microsomes and human liver microsomes in microcentrifuge tubes fortified with glutathione/N-acetyl cysteine. Nicotinamide adenine dinucleotide phosphate reduced tetrasodium salt was used as a co-factor. RESULTS: A total of six glutathione and N-acetyl cysteine conjugates of brexpiprazole metabolites were identified and characterized using ultra-high-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry. Reactive metabolite 1 (RM1), RM3, RM4 and RM6 reactive conjugates were formed due to reactive quinone-imine or quinone intermediates, while RM2 and RM5 reactive adducts were generated because of a thiophene-S-oxide intermediate. CONCLUSION: Brexpirazole is bioactivated due to the presence of a 1-(benzo[b]thiophen-4-yl)piperazine ring in its structure. In contrast to aripiprazole, the quinolinone motif was found latent towards bioactivation in brexpiprazole.

Advancements in the Analytical Quantification of Nitroxidative Stress Biomarker 3-Nitrotyrosine in Biological Matrices.

Dysfunction of the antioxidant system or mutations in the gene may result in the elevated production of certain biomarkers. 3-nitrotyrosine (3-NT) is one such promising biomarker of oxidative stress formed due to nitration of protein bound and free tyrosine residues. It has a significant potential to be exploited for the early diagnosis of diseases. There are a plethora of studies in which 3-NT has been utilized from the pharmacological perspective. However, there is a lack of studies in which the absolute concentration of 3-NT has been reported. Recent breakthrough technologies and modified analytical techniques have been reported to improve the selectivity and sensitivity of 3-NT detection. In this review, we have summarized the modifications to current analytical strategies and advancements in different approaches for 3-NT analysis. For the first time, pre-fabricated biosensors available for 3-NT have been reviewed in this article. A complete discussion on other advanced approaches such as capillary electrophoresis, electron paramagnetic resonance spectroscopy, and electron-vibration-vibration two-dimensional infrared spectroscopy for 3-NT analysis has been made. We have summarized the widest array of conventional and modern analytical techniques reported till date including the recent advancement in the field for the quantification of 3-NT in various types of biological samples.

Update on metabolism of abemaciclib: In silico, in vitro, and in vivo metabolite identification and characterization using high resolution mass spectrometry.

Abemaciclib was approved by the US Food and Drug Administration in 2015 as an advanced treatment for metastatic breast cancer. Identification and characterization of limited numbers of abemaciclib metabolites have been reported in the literature. Therefore, the current study focused on the investigation of the in vitro and in vivo metabolic fate of abemaciclib using high resolution mass spectrometry. Initially, a vulnerable site of metabolism was predicted by the Xenosite web predictor tool. Later, in vitro metabolites were identified from pooled rat liver microsomes, rat S9 fractions, and human liver microsomes. Finally, in vivo metabolites have been detected in plasma, urine, and feces matrix of male Sprague-Dawley rats. A total of 12 putative metabolites (11 phase I and 1 phase II) of abemaciclib and their metabolic pathways were proposed by considering accurate mass, mass fragmentation pattern, nitrogen rule, and ring double bonds of the detected metabolites. Abemaciclib was metabolized via hydroxylation, N-oxidation, N-dealkylation, oxidative deamination followed by reduction and sulfate conjugation. In the human liver microsomes, maximum numbers of metabolites (11 metabolites) were observed, from which M7, M8, M9, and M11 were human specific.

Edaravone-caffeine combination for the effective management of rotenone induced Parkinson's disease in rats: An evidence based affirmative from a comparative analysis of behavior and biomarker expression.

Restoration of cellular microenvironment is important in the treatment of neurodegenerative diseases for optimal functioning and survival of neurons. Oxidative stress has been proposed as one of the major pathogenic drivers in Parkinson's disease. Parkinson's model was developed by chronic administration of a pesticide rotenone that inhibits mitochondrial complex I resulting in generation of reactive oxygen species. In this study, our aim was to evaluate neuroprotective effect rendered by edaravone, a potent free radical scavenger in combination with caffeine, an effective inhibitor of adenosine A2A receptor as well as a proven antioxidant. Here we demonstrate that a three-week treatment with edaravone-caffeine combination was able to significantly diminish rotenone induced oxidative damage at the cellular level as well as muscle weakness and cognitive impairment generally associated with Parkinson's disease. This effect is attributable to edaravone's capability of scavenging the perxoynitrite free radical. Herein, we have assessed the levels of protein nitroxidation marker 3-nitrotyrosine in the striatum and lipid peroxidation marker malondialdehyde in striatum, cerebrospinal fluid, plasma and urine of rats. On the 21st day, statistical difference was observed in the striatal biomarker levels (p = 0.001) between the controls, treated and untreated groups. We discovered that when edaravone was co-administered with caffeine, the effect was more significant compared to the group solely treated with edaravone demonstrating a synergistic effect. Simultaneous therapeutic intervention with drug combination showed a pronounced decrease in oxidative damage markers as well as better muscle strength and cognition compared to the untreated groups.

In silico, in vitro and in vivo metabolite identification of brexpiprazole using ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry.

RATIONALE: Brexpiprazole is a novel serotonin-dopamine activity modulator approved by the USFDA in July 2015 for the treatment of schizophrenia and as an adjunctive therapy with other antidepressants for major depressive disorder in adults. However, limited numbers of metabolites are reported in the literature for brexpiprazole. Our prime intent behind this study is to revisit metabolite profiling of brexpiprazole and to identify and characterize all possible in vitro and in vivo metabolites. METHODS: Firstly, the site of metabolism for brexpiprazole was predicted by a Xenosite web predictor model. Secondly, in vitro metabolite profiling was performed by incubating the drug individually with rat liver microsomes, human liver microsomes and rat S9 fraction at 37°C for 1 h in incubator shaker. Finally, for in vivo metabolite identification, a 50 mg kg-1 dose of brexpiprazole was administered to male Sprague-Dawley rats and the presence of various metabolites was confirmed in rat plasma, urine and feces. RESULTS: The predicted atomic site of metabolism was obtained as a color gradient by the Xenosite web predictor tool and, from this study, probable metabolites were listed. In total, 14 phase I and 2 phase II metabolites were identified and characterized in the in vitro and in vivo matrices using ultra-high-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry (UHPLC/QTOF-MS/MS). The majority of metabolites were found in the sample incubated with human liver microsomes and in rat urine, while in the other matrices only a few metabolites were detected. CONCLUSIONS: All the 16 metabolites were identified and characterized using UHPLC/QTOF-MS/MS. The study revealed that brexpiprazole is metabolized via hydroxylation, glucuronidation, S-oxidation, N-oxidation, dioxidation, oxidative deamination, N-dealkylation, etc.

Study on interaction between palladium(ІІ)-Linezolid chelate with eosin by resonance Rayleigh scattering, second order of scattering and frequency doubling scattering methods using Taguchi orthogonal array design.

Linezolid reacted with palladium to form 1:1 binary cationic chelate which further reacted with eosin dye to form 1:1 ternary ion association complex at pH 4 of Walpole's acetate buffer in the presence of methyl cellulose. As a result not only absorption spectra were changed but Resonance Rayleigh Scattering (RRS), Second-order Scattering (SOS) and Frequency Doubling Scattering (FDS) intensities were greatly enhanced. The analytical wavelengths of RRS, SOS and FDS (λex/λem) of ternary complex were located at 538 nm/538nm, 240 nm/480 nm and 660 nm/330 nm, respectively. The linearity range for RRS, SOS and FDS methods were 0.01-0.5 µg mL(-1), 0.1-2 µg mL(-1) and 0.2-1.8 µg mL(-1), respectively. The sensitivity order of three methods was as RRS>SOS>FDS. Accuracy of all methods were determined by recovery studies and showed recovery between 98% and 102%. Intraday and inter day precision were checked for all methods and %RSD was found to be less than 2 for all methods. The effects of foreign substances were tested on RRS method and it showed the method had good selectivity. For optimization of process parameter, Taguchi orthogonal array design L8(2(4)) was used and ANOVA was adopted to determine the statistically significant control factors that affect the scattering intensities of methods. The reaction mechanism, composition of ternary ion association complex and reasons for scattering intensity enhancement was discussed in this work.