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91.
Janet Martin Stephen M. Stribbling Grace K. Poon Richard H. J. Begent Mark Napier Surinder K. Sharma C. J. Springer 《Cancer chemotherapy and pharmacology》1997,40(3):189-201
Antibody-directed enzyme prodrug therapy (ADEPT) was administered to ten patients in a phase I clinical trial. The aim was
to measure plasma levels of the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl) amino] benzoyl-l-glutamic acid (CMDA) and the bifunctional alkylating drug (CJS11) released from it by the action of tumour-localised carboxypeptidase
G2 (CPG2) enzyme. New techniques were developed to extract the prodrug and drug from plasma by solid-phase adsorbtion and
elution and to measure CPG2 activity in plasma and tissue. All extracts were analysed by high-performance liquid chromatography
(HPLC) and liquid chromatography-mass spectrometry (LC-MS). CPG2 activity was found in metastatic tumour biopsies but not
in normal tissue, indicating that localisation had been successful. The clearing agent SB43-gal, given at 46.5 mg/m2, achieved the aim of clearing non-tumour-localised enzyme in the circulation, indicating that conversion of prodrug to drug
could take place only at the site of localised conjugate. Plasma prodrug did not always remain above its required threshold
of 3 μM for the “therapeutic window” of 120 min after dosing, but the presence of residual prodrug after the first administration
of each day indicated that this could be achieved during the remaining four doses over the following 8 h. Despite considerable
inter-patient prodrug plasma concentration variability, the elimination half-life of the prodrug was remarkably reproducible
at 18 ± 8 min. Rapid appearance of the drug in plasma indicated that successful conversion from the prodrug had taken place,
but also undesirable leakback from the site of localisation into the bloodstream. However, drug plasma levels fell rapidly
by at least 50% at between 10 and 60 min with a half-life of 36 ± 14 min. Analysis of the plasma extracts by LC/MS indicated
that this technique might be used to confirm qualitatively the presence of prodrug, drug and their metabolites.
Received: 21 July 1996 / Accepted: 20 January 1997 相似文献
92.
下肢深静脉血栓形成患者血浆抗凝蛋白水平检测的临床意义 总被引:2,自引:1,他引:2
目的:探讨下肢深静脉血栓形成(LDVT)患者的发病机制,研究抗凝血酶(AT)、蛋白S(PS)、蛋白C(PC)、活化蛋白C抵抗性(APCR)在LDVT患者中的变化。方法:用ACL Puturn 型全自动血凝仪检测LDVT患者100例(初发、复发患者各73、27例)和健康者100例的AT、PS、PC活性及APCR。结果:LDVT组与正常对照组相比,LDVT复发组与初发组相比,AT、PS、PC活性明显降低,APCR阳性率明显升高,差异有统计学意义(P<0.01~0.001);100例LDVT患者中,25例有抗凝蛋白缺陷,以PS缺陷的总发生率最高,占13%(13例),其次是PC缺陷,占8%(8例),AT缺陷占5%(5例),APCR缺陷的总发生率最小,占4%(4例)。结论:先天性或获得性抗凝蛋白缺陷是LDVT发病和复发的重要机制之一。 相似文献
93.
目的:了解临床分离的肺炎克雷伯菌耐药性及主要耐药基因存在状况。方法:采用Micmsean微生物鉴定仪,微量肉汤稀释法测定肺炎克雷伯菌对21种抗生素的敏感性。采用聚合酶链反应(PCR)及测序技术分析超广谱B内酰氨酶(ESBLs),质粒介导的AmpC酶和氨基糖苷类修饰酶基因型。结果:肺炎克雷伯菌对亚胺培南全部敏感,对其他抗生素均有不同程度的耐药。60株全部扩增出TEM基因,有25株检出CTX-M-I群基因,有54株扩增出DHA基因,59株检出共3种氨基糖苷类修饰酶基因。且有22株同时携带2~6种耐药基因。对其中4株细菌进行基因型测序,证实CTX-M-I群扩增产物均为CTX-M-3;DHA扩增产物均为DHA-1;氨基糖苷类修饰酶基因分别为aac(3)-Ⅱ、aac(6′)-I和ant(3″)-I。其中CTX-M-3(AY635141)、DHA-1(AY635140)已注册GenBank(括号内为GenBank注册号)。结论:临床分离的肺炎克雷伯菌为多重耐药菌,同时存在2~6种耐药基因。 相似文献
94.
《Drug discovery today》2014,19(12):1871-1882
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ContextLiquid Chromatography Mass Spectroscopy (LC-MS/MS) is the preferred method to measure 25 hydroxyvitamin D (25OHD) levels, but laboratories are increasingly adopting automated platform assays.ObjectiveWe assessed the performance of commonly used automated immunoassays, with that of LC-MS/MS, and the National Institute of Standards and Technology (NIST) reference values, to measure 25OHD levels.Methods/SettingWe compared serum 25OHD levels obtained from 219 elderly subjects, enrolled in a vitamin D trial, using the Diasorin Liaison platform assay, and the tandem LC-MS/MS method. We also assessed the performance of the Diasorin and Roche automated assays, expressed as mean % bias from the NIST standards, based on the vitamin D External Quality Assessment Scheme (DEQAS) reports, from 2013 to 2017.ResultsSerum 25OHD levels were significantly lower in the Diasorin compared to LC-MS/MS assay at baseline, 18.5 ± 7.8 vs 20.5 ± 7.6 ng/ml (p < 0.001), and all other time points. Diasorin (25OHD) = 0.76 × LC-MS/MS (25OHD) + 4.3, R2 = 0.596. The absolute bias was independent of 25OHD values, and the pattern unfit for any cross-calibration. The proportion of subjects considered for vitamin D treatment based on pre-set cut-offs differed significantly between the 2 assays. There also was wide variability in the performance of both automated assays, compared to NIST reference values.ConclusionThe performance of most widely used automated assays is sub-optimal. Our findings underscore the pressing need to re-consider current practices with regard to 25OHD measurements, interpretation of results from research studies, meta-analyses, the development of vitamin D guidelines, and their relevance to optimizing health. 相似文献
99.
《Drug metabolism and pharmacokinetics》2018,33(2):133-140
Human hepatic cell lines are widely used as an in vitro model for the study of drug metabolism and liver toxicity. However, the validity of this model is still a subject of debate because the expressions of various proteins in the cell lines, including drug-metabolizing enzymes (DMEs), can differ significantly from those in human livers. In the present study, we first conducted an untargeted proteomics analysis of the microsomes of the cell lines HepG2, Hep3B, and Huh7, and compared them to human livers using a sequential window acquisition of all theoretical mass spectra (SWATH) method. Furthermore, high-resolution multiple reaction monitoring (MRM-HR), a targeted proteomic approach, was utilized to compare the expressions of pre-selected DMEs between human livers and the cell lines. In general, the SWATH quantifications were in good agreement with the MRM-HR analysis. Over 3000 protein groups were quantified in the cells and human livers, and the proteome profiles of human livers significantly differed from the cell lines. Among the 101 DMEs quantified with MRM-HR, most were expressed at substantially lower levels in the cell lines. Thus, appropriate caution must be exercised when using these cell lines for the study of hepatic drug metabolism and toxicity. 相似文献
100.