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61.
新型心肌显像剂[99Tcm(N)(PNP5)(DBODC)]+猪心肌显像研究 总被引:2,自引:0,他引:2
目的 评价新型心肌显像剂[99Tcm(N)(PNP=5)(DBODC)]+在猪体内的药代动力学特征及生物分布特性.方法 利用药盒法制备[99Tcm(N)(PNP5)(DBODC)]+注射液.实验动物选7头实验用成年健康中华小型猪,由耳静脉注入[99Tcm(N)(PNP5)(DBODC)]+,分别于注射后2,5,10,15,30,45,60,75,90,120,150和180 min从猪后肢静脉进行血样采集以获得药代动力学参数,同时进行胸腹部平面系列显像,以观察该药物在猪体内的生物分布和靶/非靶比值,并与99Tcm-甲氧基异丁基异腈(MIBI)显像比较(采用配对t检验).结果 [99Tcm(N)(PNP5)(DBODC)]+标记率为(95.54±0.85)%,其符合一次静脉给药的药代动力学二室模型,分布半衰期T1/2á=(2.97±0.48)min,消除半衰期T1/2a=(52.49±19.49)min,血液总清除速率(CL)=(14 314.29.±8445.79)ml/h.心、肝、肺时间-放射性曲线显示[99Tcm(N)(PNP5)(DBODC)]+肝摄取在初始时明显高于心肌,但肝内放射性清除迅速,在注射30 min后,肝内放射性已低于心肌放射性,而99Tcm-MIBI肝摄取在180 min内均高于心肌.[99Tcm(N)(PNT5)(DBODC)]+的心/肝比值在注射后30~180 min均高于99Tcm-MIBI(t值为10.395~54.482,P均<0.05).显像示在注射[99Tcm(N)(PNP5)(DBODC)]+后5~180 min均可获得清晰的心肌图像,肝内示踪剂迅速排入胆、肠系统,致使肝内放射性迅速减低,有利于减少对左室下壁的干扰.结论 [99Tcm(N)(PNP5)(DBODC)]+有望成为一种新的心肌灌注显像剂. 相似文献
62.
This study was designed to investigate the induction of CYP2E1 in obese Zucker rats and its effect on the disposition kinetics of chlorzoxazone (CZX). CZX 20mg/kg was administered to three groups of rats: normal Zucker rats fed a normal diet (ND), normal Zucker rats fed a high-fat diet (HF), and genetically obese Zucker rats fed a normal diet (OB). The values of the area under the plasma concentration-time curve from 0 to infinity (AUC(infinity)) of CZX were in the order of ND>HF>OB rats. The AUC(infinity) values of total 6-hydroxychlorzoxazone (6OHCZX-T), which is considered to be a CYP2E1 metabolic marker, were in the opposite order. The values of the AUC(infinity) ratio (6OHCZX-T/CZX) in ND, HF and OB rats were approximately 0.2, 0.3 and 0.4, respectively. The CZX concentration in fat was much higher than the concentrations in plasma, liver and kidney in all groups. Induction of CYP2E1 protein was greater in both liver and fat of OB rats than in those of HF rats. Microsomal activity of CYP2E1 in liver and fat was also in the order of OB>HF>NM rats. These results suggest that CYP2E1 may be induced in liver and fat of obese patients, thereby potentially altering the disposition kinetics of not only CZX, but also other lipophilic drugs metabolized by CYP2E1. 相似文献
63.
Ljubica Glavaš-Obrovac Mirjana Suver Sadao Hikishima Mariko Hashimoto Tsutomu Yokomatsu Lucyna Magnowska Agnieszka Bzowska 《Chemical biology & drug design》2010,75(4):392-399
Potent inhibitors of purine nucleoside phosphorylase (PNP) are expected to act as selective agents against T-cell tumours. Five compounds with guanine, three with hypoxanthine, and five with 9-deazaguanine, all connected by a linker with difluoromethylene phosphonic acid, were studied on their inhibitory potential against human and calf PNPs. Antiproliferative activity of these analogues against lymphocytes as well as lymphoma and leukaemia cells has been also investigated. All tested compounds act as multisubstrate analogue inhibitors of PNP with the apparent inhibition constants in the range 5–100 nm , and also show a slight antiproliferative activity. Analogues with 9-deazaguanine aglycone have better anti-leukaemic and anti-lymphoma activities compared to the guanine and hypoxanthine analogues, and applied in the concentration of 100 μm , caused a statistically significant decrease in the cell viability in all human leukaemia and lymphoma cells used. Despite the high PNP inhibitory potential of tested analogues, no differences were observed between the effects on the growth of tumour cells sensible to the inhibition of PNP, such as human adult T-cell leukaemia and lymphoma cells, and other investigated cells. Obtained poor effects on cell proliferation could be explained probably by a poor ability of tested compounds to penetrate cell membranes. 相似文献
64.
This report describes the evaluation of three cationic 99mTc(I)–tricarbonyl complexes — [99mTc(CO)3(L)]+ (L=N-methoxyethyl-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (ME-PNP), N-[15-crown-5)-2-yl]-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (15C5-PNP) and N-[18-crown-6)-2-yl]-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (18C6-PNP)) — as potential radiotracers for myocardial perfusion imaging. Biodistribution, imaging and metabolism studies were performed using Sprague–Dawley rats. It was found that bisphosphine ligands have a significant impact on the biodistribution characteristics and clearance kinetics of their cationic 99mTc(I)–tricarbonyl complexes. Among the three radiotracers evaluated in this study, [99mTc(CO)3(15C5-PNP)]+ has a very high initial heart uptake and is retained in the rat myocardium for >2 h. It also shows rapid clearance from the liver and lungs. The heart/liver ratio of [99mTc(CO)3(15C5-PNP)]+ is 2.5 times better than that of 99mTc-sestamibi at 30 min postinjection. [99mTc(CO)3(15C5-PNP)]+ is almost identical to 99mTcN-DBODC5 with respect to heart uptake, heart/lung ratio and heart/liver ratio. Results from metabolism studies show that there is no significant metabolism for [99mTc(CO)3(15C5-PNP)]+ in the urine, but it does show a small metabolite peak (<10%) in the radio high-performance liquid chromatography chromatogram of the feces sample at 120 min postinjection. Results planar imaging studies demonstrate that [99mTc(CO)3(15C5-PNP)]+ has a much better liver clearance profile than 99mTc-sestamibi and might give clinically useful images of the heart as early as 30 min postinjection. [99mTc(CO)3(15C5-PNP)]+ is a very promising candidate for more preclinical evaluations in various animal models. 相似文献
65.
Nitric oxide donors prevent while the nitric oxide synthase inhibitor L-NAME increases arachidonic acid plus CYP2E1-dependent toxicity 总被引:1,自引:0,他引:1
Polyunsaturated fatty acids such as arachidonic acid (AA) play an important role in alcohol-induced liver injury. AA promotes toxicity in rat hepatocytes with high levels of cytochrome P4502E1 and in HepG2 E47 cells which express CYP2E1. Nitric oxide (NO) participates in the regulation of various cell activities as well as in cytotoxic events. NO may act as a protectant against cytotoxic stress or may enhance cytotoxicity when produced at elevated concentrations. The goal of the current study was to evaluate the effect of endogenously or exogenously produced NO on AA toxicity in liver cells with high expression of CYP2E1 and assess possible mechanisms for its actions. Pyrazole-induced rat hepatocytes or HepG2 cells expressing CYP2E1 were treated with AA in the presence or absence of an inhibitor of nitric oxide synthase L-N(G)-Nitroarginine Methylester (L-NAME) or the NO donors S-nitroso-N-acetylpenicillamine (SNAP), and (Z)-1-[-(2-aminoethyl)-N-(2-aminoethyl)]diazen-1-ium-1,2-diolate (DETA-NONO). AA decreased cell viability from 100% to 48+/-6% after treatment for 48 h. In the presence of L-NAME, viability was further lowered to 23+/-5%, while, SNAP or DETA-NONO increased viability to 66+/-8 or 71+/-6%. The L-NAME potentiated toxicity was primarily necrotic in nature. L-NAME did not affect CYP2E1 activity or CYP2E1 content. SNAP significantly lowered CYP2E1 activity but not protein. AA treatment increased lipid peroxidation and lowered GSH levels. L-NAME potentiated while SNAP prevented these changes. Thus, L-NAME increased, while NO donors decreased AA-induced oxidative stress. Antioxidants prevented the L-NAME potentiation of AA toxicity. Damage to mitochondria by AA was shown by a decline in the mitochondrial membrane potential (MMP). L-NAME potentiated this decline in MMP in association with its increase in AA-induced oxidative stress and toxicity. NO donors decreased this decline in MMP in association with their decrease in AA-induced oxidative stress and toxicity. These results indicate that NO can be hepatoprotective against CYP2E1-dependent toxicity, preventing AA-induced oxidative stress. 相似文献
66.
The uptake and metabolism of vitamin B-6 by the blood cells and the distribution of the radioactive vitamin B-6 metabolites in the plasma were studied by injecting [3H]-pyridoxine in the tail vein of young adult and senescent mice, killing the mice after 15 or 30 min, and separating the B-6 metabolites by ion exchange chromatography. The blood cells of both age groups took up and metabolized the tritiated pyridoxine in essentially the same fashion. Thirty min after injection of the mice, a smaller percentage of the total radioactivity in the plasma appeared in pyridoxal-P and a larger percentage appeared in pyridoxal and pyridoxine in the senescent mice than in the young mice. 相似文献
67.
68.
目的:建立对硝基酚(PNP)溶液检测自动生化分析仪精密度方法。方法:通过酸性PNP溶液吸收峰扫描,在日立 7170自动生化分析仪上建立程序进行精密度观察,并对测定结果进行评价。结果:在酸性环境下PNP溶液最大吸收峰为 295-340nm;加入PNP溶液后的反应曲线是典型的终点比色法反应方式;连续记录30个工作日批内不精密度均未超过 1.20%,平均不精密度为0.55%;日间不精密度为2.22%。结论:PNP溶液检测自动生化分析仪精密度,方法简便,成本低 廉,能有效地反映自动生化分析仪工作状态。 相似文献
69.
Fatal graft versus host disease after platelet transfusions in a child with purine nucleoside phosphorylase deficiency 总被引:1,自引:0,他引:1
S. Strobel G. Morgan A. H. Simmonds R. J. Levinsky 《European journal of pediatrics》1989,148(4):312-314
Fatal graft versus host disease (GVHD) developed in a child with purine nucleoside phosphorylase (PNP) deficiency following an unirradiated platelet transfusion. IV treatment with an anti-T-cell monoclonal antibody (CD7) led to a transient improvement of his GVHD (Grade IV) but did not prevent the fatal outcome. This report emphasizes the need for blood products to be irradiated when cell mediated immunodeficiency is suspected, even in patients with residual immunocompetence.Abbreviations ADA
adenosine-deaminase
- CD
cluster determinant
- GVHD
graft versus host disease
- PNP
purine nucleoside phosphorylase
- SCID
severe combined immunodeficiency 相似文献
70.
Two large immunogenic and antigenic myoglobin peptides and the effects of cyclisation 总被引:2,自引:0,他引:2
D S Dorow P T Shi F R Carbone E Minasian P E Todd S J Leach 《Molecular immunology》1985,22(11):1255-1264
Peptides corresponding to sequences (72-88) and (26-54) of beef myoglobin have been synthesised in their open-chain and cyclised forms (using a disulphide bridge) and tested for their antigenicity and immunogenicity. Antibodies raised to beef myoglobin bound to both peptides but more strongly to the 29-residue than to the 17-residue peptide. Cyclisation increased the antigenicity of the larger peptide. In this form the peptide competed much more strongly than in the uncyclised form for specific antibodies to beef myoglobin. The peptides are immunogenic in mice without being coupled to a protein carrier and produce antibodies which bind to beef myoglobin. Peptide (26-54) is the more immunogenic in producing a larger antibody titre to the parent myoglobin and cyclisation again enhances this property. The findings lend weight to the view that longer peptide sequences might be expected to favour the folded state, therefore binding more strongly to antibodies raised to the native protein and eliciting a population of antibodies which contain a larger proportion specific for that conformation. Cyclisation enhances antigenicity and immunogenicity presumably by decreasing the number of degrees of conformational freedom of a peptide without excluding native-like conformations. 相似文献