A Novel Approach to Predicting P450 Mediated Drug Metabolism. CYP2D6 Catalyzed N-Dealkylation Reactions and Qualitative Metabolite Predictions Using a Combined Protein and Pharmacophore Model for CYP2D6

1999 ◽  
Vol 42 (20) ◽  
pp. 4062-4070 ◽  
Author(s):  
Marcel J. de Groot ◽  
Mark J. Ackland ◽  
Valerie A. Horne ◽  
Alexander A. Alex ◽  
Barry C. Jones
1999 ◽  
Vol 42 (9) ◽  
pp. 1515-1524 ◽  
Author(s):  
Marcel J. de Groot ◽  
Mark J. Ackland ◽  
Valerie A. Horne ◽  
Alexander A. Alex ◽  
Barry C. Jones

The Analyst ◽  
2016 ◽  
Vol 141 (10) ◽  
pp. 2940-2947 ◽  
Author(s):  
Jie Zhang ◽  
Fengming Chen ◽  
Ziyi He ◽  
Yuan Ma ◽  
Katsumi Uchiyama ◽  
...  

A novel platform for precise cell patterning and analysis in microchips was developed by combining inkjet cell-printing and microfluidic chips.


2018 ◽  
Vol 85 (1) ◽  
pp. 216-226 ◽  
Author(s):  
Andrew Rowland ◽  
Warit Ruanglertboon ◽  
Madelé Dyk ◽  
Dhilushi Wijayakumara ◽  
Linda S. Wood ◽  
...  

2021 ◽  
Vol 12 (6) ◽  
pp. 7596-7605

The management of pharmacokinetics and pharmacodynamics of drugs constitutes an approach for personalizing pharmacotherapy. This can be achieved by controlling xenobiotic metabolism. This research aimed to study the possibility of controlling the biotransformation of substances in the body through targeted regulation of intracellular signal transduction. By UPLC-MS/MS, the effect of JNK inhibitors on the metabolism of venlafaxine xenobiotic by liver cells was investigated in vitro. The blocking of JNK in hepatic homogenate cells containing the antidepressant was accompanied by an increase in the intensity of its biotransformation. There was a significant increase in forming a single pharmacologically active metabolite of O-desmethylvenlafaxine in the cell suspension and its further chemical conversion. Data from experiments indicate marked induction of venlafaxine metabolism by the JNK inhibitor. These properties of JNK inhibitors can be used to develop a novel approach to the characterization of antidepressant treatment. Also, the results indicate the prospect of studying activity modifiers of intracellular signaling molecules (in particular, mitogen-activated protein kinases) to develop methods of controlling the process of xenobiotic transformation and create a novel class of pharmaceuticals - targeted drug metabolism regulators.


2020 ◽  
Vol 48 (8) ◽  
pp. 645-654
Author(s):  
Alexander M. Horspool ◽  
Ting Wang ◽  
Young-Sun Scaringella ◽  
Mitchell E. Taub ◽  
Tom S. Chan

2019 ◽  
Vol 476 (24) ◽  
pp. 3705-3719 ◽  
Author(s):  
Avani Vyas ◽  
Umamaheswar Duvvuri ◽  
Kirill Kiselyov

Platinum-containing drugs such as cisplatin and carboplatin are routinely used for the treatment of many solid tumors including squamous cell carcinoma of the head and neck (SCCHN). However, SCCHN resistance to platinum compounds is well documented. The resistance to platinum has been linked to the activity of divalent transporter ATP7B, which pumps platinum from the cytoplasm into lysosomes, decreasing its concentration in the cytoplasm. Several cancer models show increased expression of ATP7B; however, the reason for such an increase is not known. Here we show a strong positive correlation between mRNA levels of TMEM16A and ATP7B in human SCCHN tumors. TMEM16A overexpression and depletion in SCCHN cell lines caused parallel changes in the ATP7B mRNA levels. The ATP7B increase in TMEM16A-overexpressing cells was reversed by suppression of NADPH oxidase 2 (NOX2), by the antioxidant N-Acetyl-Cysteine (NAC) and by copper chelation using cuprizone and bathocuproine sulphonate (BCS). Pretreatment with either chelator significantly increased cisplatin's sensitivity, particularly in the context of TMEM16A overexpression. We propose that increased oxidative stress in TMEM16A-overexpressing cells liberates the chelated copper in the cytoplasm, leading to the transcriptional activation of ATP7B expression. This, in turn, decreases the efficacy of platinum compounds by promoting their vesicular sequestration. We think that such a new explanation of the mechanism of SCCHN tumors’ platinum resistance identifies novel approach to treating these tumors.


2020 ◽  
Vol 51 (3) ◽  
pp. 544-560 ◽  
Author(s):  
Kimberly A. Murphy ◽  
Emily A. Diehm

Purpose Morphological interventions promote gains in morphological knowledge and in other oral and written language skills (e.g., phonological awareness, vocabulary, reading, and spelling), yet we have a limited understanding of critical intervention features. In this clinical focus article, we describe a relatively novel approach to teaching morphology that considers its role as the key organizing principle of English orthography. We also present a clinical example of such an intervention delivered during a summer camp at a university speech and hearing clinic. Method Graduate speech-language pathology students provided a 6-week morphology-focused orthographic intervention to children in first through fourth grade ( n = 10) who demonstrated word-level reading and spelling difficulties. The intervention focused children's attention on morphological families, teaching how morphology is interrelated with phonology and etymology in English orthography. Results Comparing pre- and posttest scores, children demonstrated improvement in reading and/or spelling abilities, with the largest gains observed in spelling affixes within polymorphemic words. Children and their caregivers reacted positively to the intervention. Therefore, data from the camp offer preliminary support for teaching morphology within the context of written words, and the intervention appears to be a feasible approach for simultaneously increasing morphological knowledge, reading, and spelling. Conclusion Children with word-level reading and spelling difficulties may benefit from a morphology-focused orthographic intervention, such as the one described here. Research on the approach is warranted, and clinicians are encouraged to explore its possible effectiveness in their practice. Supplemental Material https://doi.org/10.23641/asha.12290687


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