地高辛血药浓度监测及病例分析

目的 综合分析我院实施地高辛血药浓度监测的患者资料,为临床合理用药提供科学依据.方法 查阅相关患者的病历,对2008～2009年实施地高辛血药浓度监测的194例患者的资料进行综合分析,地高辛血药浓度使用荧光偏振免疫法监测.结果 在监测的194例病例结果中,共127例地高辛血药浓度在0.5～2.0 ng/mL的有效浓度范...     

血清地高辛浓度与地高辛中毒关系的探讨

目的：探讨血清地高辛浓度与地高辛临床中毒症状的关系。方法：分析４４１例患者的临床资料。结果：６６例患者（大于２．５ｎｇ．ｍｌ＾－１所５８例,小于２．５ｎｇ．ｍｌ＾－１的８例）有地高辛中毒的临床表现,占１５％。分析与地高辛中毒的有关因素结果提示,血肌酐值高的患者出现临床中毒症状的发生率高于正常者;血钾异常及合用乙胺碘呋酮、奎尼丁等药亦易发生临床中毒症状。结论：监测血清地高辛演讲结合临床对判断地高辛中     

ATP结合盒蛋白E1在真核生物中的作用

ATP结合盒（ATP-binding cassette,ABC）蛋白超家族是真核生物进化过程中最为保守的一类蛋白。ABCE1是ABC超家族中E亚家族的唯一成员,除可抑制哺乳动物核糖核酸酶L外,还参与真核生物蛋白合成的翻译起始、终止及核糖体循环,并有可能成为新的抗肿瘤靶点。本文对ABCE1的基本生物学特性及其生物学作用作一介绍。     

地高辛血药浓度监测在临床中的应用

目的：探讨地高辛血药浓度监测的临床意义,为临床合理用药提供参考。方法：采用EMIT法测定地高辛血药浓度,对50例患者的79例次m药浓度监测结果进行回顾性分析。结果：79例次地高辛血药浓度测定值在治疗浓度0．8～2．2ng·ml^-1内的共40例次,占50．63％;低于治疗浓度范围下限（〈0．8ng·ml^-1）的18例次,占22．79％;高于治疗浓度上限（〉2．2ng·ml^-1的21例次,占26．58％。性别对地高辛血药浓度兀显著影响。随年龄增大,地高辛血药浓度呈增高的趋势。结论：通过监测地高辛血药浓度说明本院应用地高辛基本合理。对高龄患者应适当减少地高辛剂量。     

影响地高辛血药浓度的因素分析

目的调查分析地高辛血药浓度的影响因素,为合理用药提供参考。方法通过Cnki、PubMed数据库中检索近年来地高辛相关文献并整理分析。结果性别、年龄、生理病理状态、剂型、药物的相互作用是影响地高辛血药浓度的重要因素。大环内酯类抗生素、硝苯地平、维拉帕米、缬沙坦、胺碘酮、利托那韦、质子泵抑制剂等可导致地高辛血药浓度显著提高。硝普钠、甲氧氯普安、莫沙必利、氢氧化铝、药用炭等可导致地高辛血药浓度显著降低。结论临床医师或药师在设计给药方案时,应结合患者的生理病理状况,结合临床表现和联合用药等因素综合评价地高辛的疗效,合理制定个性化给药方案,以达到最佳治疗效果,降低不良反应的发生。     

Assessment of genetic polymorphism associated with ATP-binding cassette transporter A1 (ABCA1) gene and fluctuations in serum lipid profile levels in patients with coronary artery disease

BackgroundCoronary artery disease (CAD) is one of the common genetic and clinical risk factors associated with cardiovascular and multifactorial disorder. ATP-binding cassette transporter A1 (ABCA1) gene plays an important role in lipid metabolism and in multiple studies associated with CAD. However, more studies are needed to identify the exact role of single nucleotide polymorphisms which may cause CAD.ObjectivesThe aim of this study is to investigate the genetic association of polymorphism g.1051G > A in the ABCA1 gene with CAD patients in the Saudi population.MethodsWe included 315 confirmed CAD cases, and 205 non-CAD or control subjects in this case-control study. DNA isolation was carried out for all registered participants and the polymorphism g.1051G > A was genotyped with Polymerase Chain Reaction followed by Restriction Fragment Length Polymorphism analysis with EcoNI restriction enzyme.ResultsModifiable risk factors such as Body Mass Index, smoking and diabetes were strongly associated and non-modifiable risk factors such as hypertension (Systolic Blood Pressure and Diastolic Blood Pressure) and serum analysis such as Fasting Blood Glucose, Total cholesterol (TC), Triglyceride (TG) and LDL-c were significantly associated in CAD cases (p < 0.05). Allele (OR-1.73;95% CI:1.33–2.26; p = 0.0004), GA vs GG (OR-2.26; 95% CI: 1.53–3.35; p = 0.0003 and dominant inheritance pattern (OR-2.23; 95% CI:1.56–3.20; p = 0.00009 was strongly associated with CAD cases and control subjects. The frequency level of use of atorvastatin was significantly different among GG, GA and AA subjects. Additionally, TC and TG levels were influenced by the presence of g.1051G > A polymorphism.ConclusionThe polymorphism g.1051G > A in the gene ABCA1 is closely associated with the existence of the CAD subjects. This polymorphism could also affect the serum levels of the lipid profile, suggesting a possible occurrence of CAD in the Saudi population.     

Effect of tiaprofenic acid on serum digoxin concentration

The effect of concomitant tiaprofenic acid (Surgam) administration (200 mg t.i.d.) on serum digoxin concentration (SDC) was evaluated in 12 healthy volunteers on digoxin maintenance treatment. During a 10-day coadministration period with tiaprofenic acid no significant increase in SDC was observed (0.97 +/- 0.24 vs. 1.12 +/- 0.21 ng/ml, p less than 0.05). Mean tiaprofenic acid concentration amounted to 2.85 +/- 1.94 micrograms/ml 14 h after last drug intake. The incidence of adverse reactions was minimal with gastrointestinal upset in one person. Tiaprofenic acid had no influence on red or white blood cell count. Thus, in contrast to various other nonsteroidal antiinflammatory drugs coadministration of tiaprofenic acid (600 mg daily) has no relevant influence on serum digoxin levels.     

Accumulation of serum lipids by vascular smooth muscle cells involves a macropinocytosis-like uptake pathway and is associated with the downregulation of the ATP-binding cassette transporter A1

Vascular smooth muscle cells (VSMC) are present in arterial intima before atherosclerotic plaques develop and are likely to be exposed to unmodified serum lipids as they enter the vessel wall. We examined the effects of sera from mice on the morphology and function of mouse VSMC. Incubation of a mouse VSMC line (MOVAS) with sera from normocholesterolemic (C57BL/6J) or hypercholesterolemic (APOE^?/?) mice caused concentration-dependent increases in lipid accumulation as measured by AdipoRed, with the extent of lipid uptake significantly greater with the latter sera type. Inhibition of c-Jun N-terminal kinases (SP600125), Src kinases (AG1879), and clathrin-dependent endocytosis (monodansylcadaverine) to disrupt scavenger receptor-mediated uptake of lipids had no effect on serum-induced lipid accumulation by VSMC. By contrast, inhibition of macropinocytosis with antagonists of PI-3 kinase (LY294002) and actin (cytochalasin D) markedly reduced lipid accumulation. Serum exposure reduced the expression of the ATP-binding cassette transporter A1, consistent with impaired cholesterol efflux, but had no effect on the expression of markers of VSMC differentiation. Moreover, the expression of several inflammation and foam cell markers was unchanged (CCL2, CCL5, and CD68) by mouse sera. The accumulation of unmodified serum lipids by VSMC involves a macropinocytosis-like uptake pathway and is associated with the downregulation of the ATP-binding cassette transporter. We speculate that VSMC may play an atheroprotective role in arterial intima by acting as a “sink” for unmodified lipids.     

Relationship of serum and myocardial digoxin concentration to electrocardiographic estimation of digoxin intoxication

Serum and myocardial digoxin levels were studied in 18 patients who came to autopsy. An independent analysis of electrocardiograms prior to death was made to ascertain the relationship between serum and tissue levels of digoxin and clinical estimation of drug toxicity. Patients with arrhythmias of digoxin toxicity had higher mean serum and tissue digoxin levels than patients without arrhythmia. There was overlap in the patient groups, however, and the differences were not statistically significant. The tissue to serum ratio was lower in the toxic patients. The latter phenomenon is unexplained but may be related to decreased tissue binding.     

CEP-33779 antagonizes ATP-binding cassette subfamily B member 1 mediated multidrug resistance by inhibiting its transport function

The overexpression of ATP-binding cassette (ABC) transporters often leads to the development of multidrug resistance (MDR), which is the major factor contributing to the failure of chemotherapy. The objective of this study was to investigate the enhancement of CEP-33779, a small-molecule inhibitor of Janus kinase 2 (JAK2), on the efficacy of conventional chemotherapeutic agents in MDR cells with overexpression of P-glycoprotein (ABCB1), multidrug resistance-associated protein 1 (ABCC1) and breast cancer resistance protein (ABCG2). Our results showed that CEP-33779, at nontoxic concentrations, significantly sensitized ABCB1 overexpressing MDR cells to its anticancer substrates. CEP-33779 significantly increased intracellular accumulation and decreased the efflux of doxorubicin by inhibiting the ABCB1 transport function. Furthermore, CEP-33779 did not alter the expression of ABCB1 both at protein and mRNA levels but did stimulate the activity of ABCB1 ATPase. CEP-33779 was predicted to bind within the large hydrophobic cavity of homology modeled ABCB1. In addition, the down-regulation of JAK2 by shRNA altered neither the expression of ABCB1 nor the cytotoxic effect of chemotherapeutic agents in ABCB1-overexpressing cells. Significantly, CEP-33779 enhanced the efficacy of vincristine against the ABCB1-overexpressing and drug resistant KBv200 cell xenograft in nude mice. In conclusion, we conclude that CEP-33779 enhances the efficacy of substrate drugs in ABCB1-overexpressing cells by directly inhibiting ABCB1 transport function. The findings encouraged to further study on the combination therapy of CEP-33779 with conventional chemotherapeutic agents in ABCB1 mediated-MDR cancer patients.     

Skeletal muscle digoxin concentration and its relation to serum digoxin concentration and cardiac effect in healthy man

Summary Blood samples and skeletal muscle biopsies (m. quadriceps femoris, vastus lateralis) were taken from seven healthy subjects for analysis of serum and skeletal muscle digoxin concentrations by radioimmunoassay using a percutaneous needle biopsy technique for muscle sampling. The subjects were investigated on two digoxin dose levels and on the third day after withdrawal of digoxin. It was found that the skeletal muscle/serum digoxin ratio was significantly higher than the corresponding ratio obtained in a previous study with muscle sampling (m. rectus abdominis) from patients during open heart surgery. The present study indicates a significant correlation between the digoxin concentrations in serum and skeletal muscle as well as between cardiac effect, measured by changes in QS₂I, and skeletal muscle digoxin concentration. A doubling of the digoxin dose gave a proportional increase in skeletal muscle digoxin concentration. The magnitude of the estimated half-life of skeletal muscle digoxin was the same as previously reported for serum or plasma digoxin.     

492例地高辛血药浓度监测病例分析

地高辛是临床常用的强心苷之一。其治疗有效浓度范围为０．８～２．０ｎｇ／ｍｌ。本文总结分析了用ＴＤｘ测定的地高辛血浓病例４９２例，其中测定结果低于０．８ｎｇ／ｍｌ２１７例，占４４．１％，高于２．０ｎｇ／ｍｌ４６例，占９．４％，出现中毒症状有２０例，占４．３％。同时对产生上述结果的原因作了进一步的分析探讨。     

Dopamine and opioid gene variants are associated with increased smoking reward and reinforcement owing to negative mood

Negative mood increases smoking reinforcement and risk of relapse. We explored associations of gene variants in the dopamine, opioid, and serotonin pathways with smoking reward ('liking') and reinforcement (latency to first puff and total puffs) as a function of negative mood and expected versus actual nicotine content of the cigarette. Smokers of European ancestry (n=72) were randomized to one of four groups in a 2x2 balanced placebo design, corresponding with manipulation of actual (0.6 vs. 0.05 mg) and expected (told nicotine and told denicotinized) nicotine 'dose' in cigarettes during each of two sessions (negative vs. positive mood induction). Following mood induction and expectancy instructions, they sampled and rated the assigned cigarette, and then smoked additional cigarettes ad lib during continued mood induction. The increase in smoking amount owing to negative mood was associated with: dopamine D2 receptor (DRD2) C957T (CC>TT or CT), SLC6A3 (presence of 9 repeat>absence of 9), and among those given a nicotine cigarette, DRD4 (presence of 7 repeat>absence of 7) and DRD2/ANKK1 TaqIA (TT or CT>CC). SLC6A3, and DRD2/ANKK1 TaqIA were also associated with smoking reward and smoking latency. OPRM1 (AA>AG or GG) was associated with smoking reward, but SLC6A4 variable number tandem repeat was unrelated to any of these measures. These results warrant replication but provide the first evidence for genetic associations with the acute increase in smoking reward and reinforcement owing to negative mood.     

人膜转运蛋白ABCA1表达上调剂的筛选与鉴定

人ATP结合盒转运体A1(ATP-binding cassette transporter A1,ABCA1)可介导细胞内磷脂和游离胆固醇转运至贫脂或无脂的载脂蛋白A-I(apolipoprotein A-I,apoA-I),从而促进高密度脂蛋白(high density lipoprotein,HDL)生成,启动胆固醇逆转运过程,在机体清除多余脂质的过程中发挥重要作用。因此,本研究以ABCA1为靶点,前期建立了ABCA1上调剂抗动脉粥样硬化(atherosclerosis,AS)药物筛选模型,以期寻找具有新作用机制的抗AS药物。在此研究中,利用该模型对1 600个化合物进行筛选,发现2030421B上调活性大于50%,其EC50为0.50μg.mL-1。进一步研究发现,2030421B不仅能上调ABCA1的mRNA以及蛋白水平,而且能使小鼠巨噬细胞RAW264.7内胆固醇流出增加,脂滴量减少,是具有较好效果的ABCA1上调剂。     

Neratinib reverses ATP-binding cassette B1-mediated chemotherapeutic drug resistance in vitro, in vivo, and ex vivo

Neratinib, an irreversible inhibitor of epidermal growth factor receptor and human epidermal receptor 2, is in phase III clinical trials for patients with human epidermal receptor 2-positive, locally advanced or metastatic breast cancer. The objective of this study was to explore the ability of neratinib to reverse tumor multidrug resistance attributable to overexpression of ATP-binding cassette (ABC) transporters. Our results showed that neratinib remarkably enhanced the sensitivity of ABCB1-overexpressing cells to ABCB1 substrates. It is noteworthy that neratinib augmented the effect of chemotherapeutic agents in inhibiting the growth of ABCB1-overexpressing primary leukemia blasts and KBv200 cell xenografts in nude mice. Furthermore, neratinib increased doxorubicin accumulation in ABCB1-overexpressing cell lines and Rhodamine 123 accumulation in ABCB1-overexpressing cell lines and primary leukemia blasts. Neratinib stimulated the ATPase activity of ABCB1 at low concentrations but inhibited it at high concentrations. Likewise, neratinib inhibited the photolabeling of ABCB1 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner (IC(50) = 0.24 μM). Neither the expression of ABCB1 at the mRNA and protein levels nor the phosphorylation of Akt was affected by neratinib at reversal concentrations. Docking simulation results were consistent with the binding conformation of neratinib within the large cavity of the transmembrane region of ABCB1, which provides computational support for the cross-reactivity of tyrosine kinase inhibitors with human ABCB1. In conclusion, neratinib can reverse ABCB1-mediated multidrug resistance in vitro, ex vivo, and in vivo by inhibiting its transport function.     

188例次地高辛血药浓度监测分析

目的总结本院地高辛血药浓度监测情况,为临床提供参考.方法对2002年188例次地高辛血药浓度监测的目的、采血时间、血药浓度结果分布、病人临床情况以及临床对本部门所提用药建议的采纳情况进行统计分析.结果地高辛血药浓度监测目的以诊断中毒为多,占54.3%;采血时间除个别外,大多数符合要求.血药浓度结果,低于0.5 ng/ml的有31例次(占16.5%);在0.5～2.0 ng/ml范围内的有123例次(占65.4%);高于2.0 ng/ml的有34例次(占18.1%).除少数病例外,临床疗效及毒性反应与浓度结果有较好的相关性.共提出个体化给药方案75项,有36项(占48%)被采纳.结论进行血药浓度监测对安全有效地应用地高辛十分必要.在判断中毒或设计个体化给药方案时,需综合考虑各种因素的影响.     

地高辛血药浓度与临床疗效关系

目的:研究地高辛浓度与临床疗效之间的关系.方法:将353例口服地高辛的充血性心衰患者分成3组:有效组、无效组及中毒组.应用放射免疫法(RIA)对其稳态血药浓度进行测定同时观察疗效.结果;平均血药浓度有效组为(1.07±0.50)ng/ml,无效组为(0.97±0.54)ng/ml,中毒组为(2.74±1.35)ng/ml.有效组与中毒组之间血药浓度有显著性差异(P<0.001).有效组与中毒组之间单位剂量(mg·kg~(-1)·d~(-1))有显著性差异(P<0.01).有效组单位剂量为(0.004 0±0.001 2)mg·kg~(-1)·d~(-1),中毒组为(0.004 7±0.001 9)mg·kg~(-1)·d~(-1).结论:地高辛血药浓度的监测可以指导临床医生合理用药、提高疗效、避免或减少不良反应.