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The objective of the present study was to assess the allelic variations of Cytochrome P450 (CYP) enzymes Cytochrome P450 2C19 (CYP2C19), Cytochrome P450 2C9 (CYP2C9), and Cytochrome P450 2D6 (CYP2D6) as they play a major role in drug metabolism. The interindividual genetic variabilities of these enzymes can account for different responsiveness as well as concentration fluctuations for a particular drug.During the period of 2017 to 2018 a total of 54 patients have received pharmacogenetic testing at the Department of Genetics and Molecular Medicine at Kaunas Clinics. According to the genotype-metabolic phenotypes of CYP2C19, CYP2D6, CYP2C9 enzymes patients were classified according to the guidelines by Clinical Pharmacogenetics Implementation Consortium (CPIC): normal metabolizers (NMs), intermediate metabolizers (IMs), rapid metabolizers (RMs), ultrarapid metabolizers (UMs), and poor metabolizers (PMs).CYP2C19 enzyme allelic distribution: 18 patients (33.33%) with ∗1/∗1 genotype were NMs; 14 patients (25.93%) with ∗1/∗2; ∗2/∗17 genotypes were classified as IMs; 15 patients (27.78%) possessed ∗1/∗17 genotype and were RMs; 4 patients (7.4%) had ∗17/∗17 genotype with increased enzyme activity compared with RMs, were classified as UMs; 3 patients (5.56%) had ∗2/∗2 genotype and were marked as PMs. CYP2D6 enzyme allelic distribution: 26 patients (48.148%) contained ∗1/∗1,∗2/∗2,∗1/∗2,∗1/∗41,∗2/∗41 genotypes with normal enzymatic function so were accounted as NMs; 21 patients (38.89%) with ∗1/∗5, ∗2/∗4, ∗10/∗41, ∗1/∗4, ∗1/∗3, ∗2/∗5, ∗2/∗4, ∗2/∗6 genotypes were accounted as IMs; 2 patients (3.7%) possessed ∗2XN genotype and were accounted as UMs and 5 patients (9.26%) possessed ∗4/∗5,∗4/∗10,∗4/∗9,∗4/∗41 genotypes and had non-functional enzymatic activity so were accounted as PMs; CYP2C9 enzyme allelic distribution: 44 patients (81.48%) with∗1/∗1 genotype were NMs; 10 patients (18.52%) with ∗1/∗2;∗1/∗3 genotypes were IMs.The results of our study indicate that deviations from the normal enzymatic activity is common amongst Lithuanian people and combinatory genotyping of CYP2D6, CYP2C9, and CYP2C19 has to be promoted as an advanced method because of most commonly prescribed medicines like analgesics, antihypertensive, antidepressants are metabolized by multiple pathways involving enzymes in the CYP450 family. 相似文献
3.
《Drug discovery today》2022,27(8):2373-2385
Autophagy, an evolutionarily highly conserved cellular degradation process, plays the Janus role (either cytoprotective or death-promoting) in colorectal cancer, so the targeting of several key autophagic pathways with small-molecule compounds may be a new therapeutic strategy. In this review, we discuss autophagy-associated cell death pathways and key cytoprotective autophagy pathways in colorectal cancer. Moreover, we summarize a series of small-molecule compounds that have the potential to modulate autophagy-associated cell death or cytoprotective autophagy for therapeutic purposes. Taken together, these findings demonstrate the Janus role of autophagy in colorectal cancer, and shed new light on the exploitation of a growing number of small-molecule compounds to target autophagy in future cancer drug discovery. 相似文献
4.
The effects of varying clinically relevant patterns of anaesthetic-vasoconstrictor combinations used for peri-radicular surgery on plasma concentrations of catecholamines and haemodynamic responses was studied in the canine model. Five mongrel dogs were anaesthetized with sodium pentobarbital. A femoral canula was inserted to measure central blood pressure and an ECG was used to monitor heart rate and any associated arrhythmias. Femoral venous blood samples were drawn before initial injection and at 3 and 10 min after injections. Plasma catecholamine concentrations were determined using high pressure liquid chromatography (HPLC). Injection protocols used three time periods, 30, 60 and 90s, with solutions containing 1:100000 and 1:50000 adrenaline. No significant changes in heart rates or presence of arrythymias were noted over the experimental protocol. Catecholamine levels in pico moles mL-1 were within the normal range at the 3-min sample level. At the 10-min sample time there was a more erratic range of concentrations, with most samples within the normal range. This may have been due to endogenous release of catecholamines in specific animals. The data identified trends in both the haemodynamic parameters and plasma catecholamine levels that can legitimately support the careful use of higher levels of a vasoconstrictor when patient profiles and surgical needs dictate. 相似文献
5.
目的:比较牛膝生品、蒸馏水炙品及不同乙醇浓度酒炙品指纹图谱差异,研究不同乙醇浓度酒炮炙对牛膝饮片的影响。方法:采用HPLC,以岛津VP-ODS(4.6 mm×250 mm,5μm)为色谱柱,乙腈-水为流动相梯度洗脱,流速0.8 m L/min,柱温25℃,检测波长243 nm,进样量15μL,采集90 min。结果:牛膝各酒炙品大部分峰面积较生品的要稍高,蒸馏水炙品的较生品稍低,但不是很明显。结论:酒炙有利于本实验建立指纹图谱中的牛膝大部分有效成分的溶出,高浓度乙醇炙品在有效成分溶出方面优于低浓度乙醇炙品。 相似文献
6.
Ghrelin is a physiological regulator of insulin release in pancreatic islets and glucose homeostasis
Ghrelin, an acylated 28-amino acid peptide, was isolated from the stomach as the endogenous ligand for the growth hormone (GH) secretagogue receptor (GHS-R). Circulating ghrelin is produced predominantly in the oxyntic mucosa of stomach. Ghrelin potently stimulates GH release and feeding, and exhibits positive cardiovascular effects, suggesting a possible clinical application. Low plasma ghrelin levels are associated with elevated fasting insulin levels and insulin resistance, suggesting both physiological and pathophysiological roles for ghrelin in glucose metabolism. Here, we review the physiological role of ghrelin in the regulation of insulin release and glucose metabolism, and a potential therapeutic avenue to treat type 2 diabetes by manipulating ghrelin and/or its signaling. Ghrelin inhibits insulin release in mice, rats and humans. The signal transduction mechanisms of ghrelin in islet β-cells are distinct from those utilized in GH-releasing and/or GHS-R-expressing cells. Ghrelin is expressed in pancreatic islets and released into pancreatic microcirculations. Pharmacological and genetic blockades of islet-derived ghrelin markedly augment glucose-induced insulin release in vitro. In high-fat diet-induced mildly obese mice, ghrelin-deficiency enhances insulin release and prevents impaired glucose tolerance. Thus, manipulation of insulinostatic function of ghrelin — GHS-R system, particularly that in islets, could optimize the amount of insulin release to meet the systemic demand, providing a potential therapeutic application to prevent type 2 diabetes. 相似文献
7.
Gopalai AA Senanayake SM Kiong LC Gouwanda D 《Journal of bodywork and movement therapies》2011,15(4):453-464
A method for assessing balance, which was sensitive to changes in the postural control system is presented. This paper describes the implementation of a force-sensing platform, with force sensing resistors as the sensing element. The platform is capable of measuring destabilized postural perturbations in dynamic and static postural conditions. Besides providing real-time qualitative assessment, the platform quantifies the postural control of the subjects. This is done by evaluating the weighted center of applied pressure distribution over time. The objective of this research was to establish the feasibility of using the force-sensing platform to test and gauge the postural control of individuals. Tests were conducted in Eye Open and Eye Close states on Flat Ground (static condition) and the balance trainer (dynamic condition). It was observed that the designed platform was able to gauge the sway experienced by the body when subject’s states and conditions changed. 相似文献
8.
《Biomaterials》2015
KLD-12 (KLD) is a 12-residue self-assembling peptide that can adopt nano-structures and is known for its tissue-engineering properties. Our objective was to introduce antimicrobial attribute to KLD which would help in preventing secondary infection associated with external application of such tissue engineering materials. Considering the net charge of KLD-12, varying number of cationic arginine residues were added to its N-terminus. KLD variants showed appreciable bactericidal properties without any significant increase in cytotoxicity against tested mammalian cells. Further, these variants adopted β-sheet structures and self-assembled into nano-structures comparable to that of KLD. Interestingly, the KLD variants with two (KLD-2R) and three (KLD-3R) arginine residues added to its N-terminus showed significant osteogenic effect which was comparable or better than the original peptide as evident from the alkaline phosphatase activity assay, mineralized nodule formation and expression of different osteogenic genes. Particularly, application of KLD-2R in rats to the site of a drill-hole (0.8 mm diameter) that was created in the femur metaphysis displayed significantly higher bone regeneration compared to that of KLD. The results demonstrate a simple way to improve biological property of a self-assembling peptide with tissue engineering property. 相似文献
9.
《药学学报(英文版)》2020,10(10):1835-1845
Repurposing small molecule drugs and drug candidates is considered as a promising approach to revolutionise the treatment of snakebite envenoming. In this study, we investigated the inhibiting effects of the small molecules varespladib (nonspecific phospholipase A2 inhibitor), marimastat (broad spectrum matrix metalloprotease inhibitor) and dimercaprol (metal ion chelator) against coagulopathic toxins found in Crotalinae (pit vipers) snake venoms. Venoms from Bothrops asper, Bothrops jararaca, Calloselasma rhodostoma and Deinagkistrodon acutus were separated by liquid chromatography, followed by nanofractionation and mass spectrometry identification undertaken in parallel. Nanofractions of the venom toxins were then subjected to a high-throughput coagulation assay in the presence of different concentrations of the small molecules under study. Anticoagulant venom toxins were mostly identified as phospholipases A2, while procoagulant venom activities were mainly associated with snake venom metalloproteinases and snake venom serine proteases. Varespladib was found to effectively inhibit most anticoagulant venom effects, and also showed some inhibition against procoagulant toxins. Contrastingly, marimastat and dimercaprol were both effective inhibitors of procoagulant venom activities but showed little inhibitory capability against anticoagulant toxins. The information obtained from this study aids our understanding of the mechanisms of action of toxin inhibitor drug candidates, and highlights their potential as future snakebite treatments. 相似文献
10.