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1.
6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT1513 and NUDT1512 genotypes were at a 10–15 fold higher risk of severe neutropenia than those of the wild-type during the early months of the maintenance phase. Risk of neutropenia was not significantly increased in patients with other NUDT15 variants as well as in patients with TPMT, ITPA or ABCC4 variants. These results suggest that NUDT15 polymorphisms particularly, NUDT1513 and NUDT1512, play major roles in 6-MP-induced severe hematotoxicity even when using a standard low dosage of 6-MP and genotyping of these variants is necessary in order to obtain precise tolerance doses and avoid severe hematotoxicity in pediatric patients. 相似文献
2.
《Drug metabolism and pharmacokinetics》2019,34(5):308-316
LC-MS quantification of drug metabolites is sometimes impeded by the availability of internal standards that often requires customized synthesis and/or extensive purification. Although isotopically labeled internal standards are considered ideal for LC-MS/MS based quantification, de novo synthesis using costly isotope-enriched starting materials makes it impractical for early stage of drug discovery. Therefore, quick access to these isotope-enriched compounds without chemical derivatization and purification will greatly facilitate LC-MS/MS based quantification. Herein, we report a novel 18O-labeling technique using metabolizing enzyme carboxylesterase (CES) and its potential application in metabolites quantification study. Substrates of CES typically undergo a two-step oxygen exchange with H218O in the presence of the enzyme, generating singly- and doubly-18O-labeled carboxylic acids; however, unexpected hydrolytic behavior was observed for three of the test compounds – indomethacin, piperacillin and clopidogrel. These unusual observations led to the discovery of several novel hydrolytic mechanisms. Finally, when used as internal standard for LC-MS/MS based quantification, these in situ labeled compounds generated accurate quantitation comparable to the conventional standard curve method. The preliminary results suggest that this method has potential to eliminate laborious chemical synthesis of isotope-labeled internal standards for carboxylic acid-containing compounds, and can be developed to facilitate quantitative analysis in early-stage drug discovery. 相似文献
3.
应用脉冲多普勒超声心动图对30例使用1,6-二磷酸果糖的肺炎心衰患儿进行心室舒缩功能指标的观测,并以20例常规治疗的心衰患儿及20例正常儿为对照组,评价1,6-二磷酸果糖的疗效。结果表明,1,6-二磷酸果糖能明显改善PEP、PEP/ET、PEP/R-R、FVI和SV等心室收缩功能指标及PFVE、E/A、PFVA等心室舒张功能指标,使心功能恢复正常。1,6-二磷酸果糖对肺炎心衰引起的心肌缺血、缺氧有保护作用。 相似文献
4.
5.
目的探讨1,6-二磷酸果糖(FDP)治疗新生儿缺氧缺血性脑病(HIE)合并心肌损伤的疗效.方法随机分成治疗组和对照组,均给予常规治疗,治疗组加用FDP 0.25~0.4g/(kg·次),1 次d静滴,10 d为一疗程,治疗前后均进行心肌酶测定.结果治疗组临床症状改善及心肌酶恢复效果均优于对照组,两组差异有显著性(P<0.05).结论 FDP对HIE时的脑损伤及心肌损伤均有良好效果. 相似文献
6.
The kinetic dependence of the rate of oxidative phosphorylation (ADP/t) on the concentration of exogenous ADP has been mathematically analyzed in the brain mitochondria. This relationship has been approximated by a mathematic model under various vital conditions. We propose an analytical approach to calculating the characteristics of oxidative phosphorylation and predicting the kinetics of oxidative ATP synthesis in brain mitochondria of animals subjected to hypoxia. 相似文献
7.
Summary— Experiments were designed to determine whether or not indapamide, an antihypertensive agent with vasodilator properties, inhibits endothelium-dependent contractions. Rings of aortae with and without endothelium from spontaneously hypertensive rats (SHR) were suspended in conventional organ chambers for the measurement of isometric force. Acetylcholine and adenosine diphosphate-β-S in the presence of a nitric oxide synthase inhibitor, caused endothelium-dependent contractions, which were inhibited by indapamide. The compound (10−4 M) also slightly reduced the contractions of rings without endothelium evoked by U-46,619, which activates thromboxane-endoperoxide receptors. These results demonstrate that indapamide inhibits endothelium-dependent contractions in the SHR aorta, and suggest that the inhibition is due, at least in part, to the action of the drug on the hypertensive vascular smooth muscle. 相似文献
8.
目的 探讨癌胚抗原相关细胞黏附分子(CEACAM1)源性多肽KM17对血小板聚集、释放、黏附功能的影响。方法 采用血小板聚集仪观察多肽KM17对凝血酶、胶原、花生四烯酸(AA)、二磷酸腺苷(ADP)等激动剂诱导的血小板聚集的影响;流式细胞术观察多肽KM17对ADP激活血小板后P-选择素释放的影响;显微镜下观察多肽KM17对血小板静态黏附于胶原基质的影响。结果 多肽KM17能显著促进ADP诱导的血小板聚集且呈剂量依赖(P <0.05),而对AA、胶原及凝血酶诱导的血小板聚集差异均无统计学意义(P>0.05);此外,多肽KM17对ADP激活血小板后P-选择素释放及血小板静态黏附于胶原基质的差异也无统计学意义(P>0.05)。结论 多肽KM17可明显促进ADP诱导的血小板聚集,但对ADP活化血小板后P-选择素释放及血小板静态黏附于胶原基质未见明显作用。 相似文献
9.
Yuji Okuyama Mitsuhiko Yamada Chikako Kondo Eisaku Satoh Shojiro Isomoto Takashi Shindo Yoshiyuki Horio Masafumi Kitakaze Masatsugu Hori Y. Kurachi 《Pflügers Archiv : European journal of physiology》1998,435(5):595-603
The effects of potassium channel opening drugs and intracellular nucleotides on the ATP-sensitive K+ (KATP) channel composed of SUR2A and Kir6.2 in HEK293T cells were examined using the patch-clamp technique. The SUR2A/Kir6.2 channel
was activated effectively by pinacidil, marginally by nicorandil but not by diazoxide. The pinacidil-activated channel currents
were inhibited by glibenclamide with a K
i value of 160 nM. Upon formation of inside-out (I-O) patches, spontaneous openings of the channels appeared, which were inhibited
by intracellular ATP (ATPi) equipotently in the presence and in the absence of intracellular Mg2+ (Mg2+
i). The channel activity ran-down gradually in I-O patches. The run-down channels could be reactivated by ATPi only in the presence of Mg2+
i. Uridine 5’-diphosphate (UDP) antagonized the ATPi-mediated inhibition of the channel activity before run-down. After run-down, UDP activated the channel without antagonizing
ATPi-mediated channel inhibition. Thus, the SUR2A/Kir6.2 reproduced the major properties of the native cardiac KATP channel well in terms of nucleotide regulation and pharmacology, and therefore can be a useful tool with which to elucidate
the molecular mechanisms characterizing the KATP channel.
Received: 24 October 1997 / Received after revision and accepted: 4 December 1997 相似文献
10.
Consumption of diphosphate nucleosides is investigated by histochemical methods in rat and cat nervous system. Results show NDP-ase is effectively in histological sections from animals previously perfused with glutaraldehyde or formaldehyde. Histochemical reaction is increased in presence of Ca++, Mg++, Mn++ or imidazole and inhibited by L-DOPA and Noradrenaline in incubation medium. A comparative study of TPP-ase and NDP-ase activities to dilucidate the identity of both enzymes is described. 相似文献