Effect of a protein binding change on unbound and total plasma concentrations for drugs of intermediate hepatic extraction

For substances eliminated from blood by the liver, the effect of a change in unbound fraction of drug (fu _b )on steady state total (C _b )and unbound (Cu _b )blood concentrations has hitherto only been considered for the two limiting cases, i.e., at the upper and lower extremes of hepatic intrinsic clearance (CL _int ).For a substance of very low CL _int ,if fu _b changes, C _t will change and Cu _b will remain constant, whereas if CL _int isvery high, Cu _b will change and C _b will remain constant.The present study defines the effects of a change in fu _b on C _b and Cu _b over the whole CL _int range. Computer simulations were undertaken which predicted that, for a given change in fu _b ,absolute and relative changes in C _b would decreasenonlinearly with increasing CL _{int, twhile the relative change in} Cu _{b would} increasewith CL _int .The absolute change in Cu_b would be independent of CL _int .Significant changes in C_b and Cu _{b would be observed at intermediate values of} CL _{int not just at the high and low extremes. These theoretical predictions were investigated experimentally in the isolated perfused rat liver by examining the effects of a change in} fu _{b of sodium taurocholate a substance with intermediate} CL _int (such that at fu _b =0.27,hepatic extraction ratio=0.71) induced by concurrent administration of sodium oleate. Sodium 24- ¹⁴ C-taurocholate (specific activity 52 Ci/mmol) was infused into the reservoir in a recycling system at 30 mol/hr for 105 min (n=6). At 45 min a bolus dose of sodium oleate (50 mmol) was administered to the reservoir, followed by a constant infusion of 143 mmol/hr for 1 hr. Following the administration of oleate, taurocholate fu _{b fell promptly by 55% (0.27–0.12). There was a relative increase of taurocholate} C _{b of 22.7% and a relative decrease in} Cu _{b of 45.4%, in accordance with the simulations (p<0.05). We conclude that important changes in unbound steady-state concentration, the pharmacologically active moiety, can occur upon changes in unbound fraction with compounds of intermediate hepatic intrinsic clearance}.This study was supported by the National Health and Medical Research Council of Australia.     

胚胎早期胰腺发育中相关因子表达的变化

目的 探讨人胚胎胰腺发育过程中相关因子表达的变化，为胚胎胰腺移植治疗糖尿病提供基础性研究。方法 对7～12周胎龄段的胰腺采用免疫组化S-ABC法分析胰腺发育中相关因子的表达变化、胰岛的分化和形成。结果 胰岛素、胰升糖素、生长激素抑制因子及细胞角蛋白在胚胎胰腺发育中7周开始表达，与胰岛的分化和形成一致，随着胎龄的增加表达增强；IGF-Ⅰ及Ⅶ因子在胚胎12周时出现在胰腺间质内。结论 胰岛素、胰升糖素、细胞角蛋白和IGF-Ⅰ在人胚胎胰腺的发育中起着重要的调控作用，与胰腺内外分泌腺的分化和形成有关；12周后的胚胎胰腺可以作为胚胎胰腺移植的供体。     

一氧化氮在大鼠胰腺缺血/再灌注中的变化及作用

目的:探讨一氧化氮(NO)在大鼠胰腺缺血/再灌注损伤中的变化及作用.方法:雄性Wistar大鼠随机分成3组:A、B组胰腺缺血30 min后,再灌注2,4,6,12,24h.B组再灌注前使用诱导型一氧化氮合酶(iNOS)抑制剂,A组仅给与生理盐水.C组仅行假手术.进行大鼠血清中NO水平和淀粉酶活性检测,胰腺组织形态学观察和免疫组化分析.结果:再灌注4 h后,A组iNOS表达于胰腺组织,B组无表达.此时A组NO水平达到高峰,淀粉酶活性开始升高,均高于B组(P＜0.01).再灌注6 h后,A组显微镜下观察到胰腺损伤的表现,B组未见.C组无iNOS表达,血清NO水平和淀粉酶活性均在正常范围.结论:随着再灌注时间的延长,iNOS表达于胰腺组织,NO在大鼠胰腺缺血/再灌注损伤中的有害作用占主导地位.     

磁共振诊断胰腺癌的价值

目的：总结胰腺癌在磁共振（MRI）的表现,探讨MRI诊断胰腺癌的价值。方法：回顾性分析56例胰腺癌患者的MRI资料,与手术及病理结果对照,总结磁共振诊断胰腺癌的经验。结果：本组56例胰腺癌患者31例行手术治疗,术后病理确诊腺癌26例,腺鳞癌5例。25例因淋巴结转移或远处脏器转移而放弃手术治疗,经病理组织活检而确诊。MRI检出53例,诊断符合率为94．6％（53／56）。误诊3例。结论：MRI检查对胰腺癌具有较高的诊断价值,可以为临床诊断和选择治疗方案提供有价值的参考依据。     

The utility of DW-MRI in the diagnosis of pancreatic focal lesions

Background

Early diagnosis is crucial in management of pancreatic malignancy. DWMRI could be used in differentiating pancreatic lesions and judge about tumor aggressiveness.

Functional assessment of pancreatic parenchyma after secretin administration using serial T2-weighted echo-planar magnetic resonance imaging

Signal intensity (SI) changes of pancreatic parenchyma were evaluated after intravenous administration of secretin using T2-weighted single-shot spin-echo echo-planar imaging (EPI) to assess this method as a magnetic resonance (MR) test of pancreatic exocrine function. Nine volunteers were studied with serial single-shot EPI of the pancreas for 15 minutes after the injection of secretin or saline. The normal pattern of pancreatic SI change was demonstrated after intravenous injection of secretin, a single peak at 3-4 minutes in the head, body, and tail, followed by a gradual decrease in SI. Saline injection did not induce a significant SI change. There was no statistical difference in the peak contrast ratios (first mean, 1.21-1.25, vs. second mean, 1.18-1.22) and peak times (first mean, 3.2-3.7 minutes, vs. second mean, 3.1-3.6) in a repeat study. By evaluating the pattern of time-response curves obtained from serial T2-weighted EPI after secretin injection, pancreatic exocrine function may be directly assessed at the level of the head, body, and tail.     

胰腺实性假乳头状瘤临床病理特点及其诊治

目的探讨胰腺实性假乳头状瘤临床病理特点及其诊治。方法回顾性分析19例胰腺实性假乳头状瘤患者的临床病理资料。结果上腹疼痛14例,腹部肿块12例,影像学均能发现腹部肿块但不能明确诊断。肿块平均直经10．3cm,包膜完整10例,包膜不完整9例,质地呈实性8例,呈囊实性11例。快速冰冻病理10例,6例获得确诊。病理特征为肿瘤细胞围绕纤细血管轴心形成特征性的假乳头状结构,细胞形态一致,异型不明显。4例证实有胰腺和血管浸润。11例免疫组化结果是：波形蛋白（Vimentin）、神经元特异性烯醇化酶（NSE）、a1抗胰蛋白酶（a1-AT）、突触素（Syn）、孕激素（PR）为阳性,上皮膜抗原（EMA）、雌激素（ER）、嗜铬颗粒素A（CgA）、S-100蛋白为阴性。6例行胰十二指肠切除术,7例行肿瘤局部切除术,5例行胰体尾加脾切除术,1例胰体部肿瘤行胰腺阶段切除术。18例获随访,中位随访时间41（2-103）个月,肿瘤无复发,除1例出现营养不良外,余患者生存满意。结论胰腺实性假乳头状瘤为低度恶性肿瘤,确诊需依赖病理组织学检查。手术切除是治疗本病的良好方法。     

Catechol‐O‐methyltransferase,a new target for pancreatic cancer therapy

Catechol‐O‐methyltransferase (COMT) is an important molecule in different types of cancers. Its biological effect and therapeutic significance, however, rarely been investigated fully in pancreatic cancer. Immunohistologically, high COMT expression was significantly correlated with the longer overall survival of patients (P < 0.05), indicating its protective nature. The effects of COMT on cell growth, apoptosis, and invasion were evaluated using overexpression and silencing methods. In detail, we carried out experiments using one stably transduced and two transiently transfected pancreatic cancer cell lines in vitro, and one stably transduced cell line in vivo mice xenograft models. In vitro experiments showed that COMT inhibited cell proliferation, enhanced gemcitabine‐induced apoptosis, and inhibited cell invasion in stably transduced and transiently transfected cell lines by regulating the PI3K/Akt pathway, p53, and E‐cadherin. The COMT overexpressed and silenced cell lines showed significantly inhibited and enhanced growth capacities in in vivo xenograft models, respectively. In conclusion, COMT suppressed pancreatic cancer and its high expression predicted longer survival time. The interaction of COMT with the PI3K/Akt pathway makes it a potential target for therapy.     

糖尿病脑内胰岛移植临床初步研究(附三例报告)

本文报告胰岛细胞脑内移植治疗I型糖尿病共3例,分别经过3个月、4个月、6个月的临床观察,其临床症状明显改善或消失,空腹血糖由移植前平均12.38mmol/L下降至7.77mmol/L;3例患者普通胰岛素用量平均每日62.3~u,移植后第21～30天均完全停用胰岛素,其中1例已持续撤离胰岛素治疗达5个月。观察结果提示:胰岛移植物在患者的脑内成活,并具有良好的内分泌功能。     

Proportionate cancer mortality among workers in the Belarussian tanning industry

BACKGROUND: The tanning industry involves many occupational exposures. This study evaluates proportionate cancer mortality among workers employed in the Belarussian tanning plant in Minsk. METHODS: A total of 768 workers with seniority of not less than 6 months who were hired after January 1, 1953 and died before December 31, 2000 was investigated. Proportionate mortality ratios (PMRs) were calculated using the population of Minsk to generate expected numbers. RESULTS: Among women employed in the tannery, there was a significant excess of pancreatic cancer, based on eight deaths (expected = 2.56, PMR = 3.13, 95% CI = 1.35-6.17). Six of the eight pancreatic cancer deaths occurred among women occupied in dyeing-stuffing workshops (expected = 1.64, PMR = 3.67, 95% CI = 1.34-7.97), all among workers hired between 1962 and 1984 (expected = 1.06, PMR = 6.54, 95% CI = 2.6-13.4). CONCLUSIONS: Women in this tanning industry cohort experienced excess mortality of cancer of the pancreas, with suggested increases of corpus and cervix uteri, melanoma, and kidney cancers. For men, an insignificant increase in PMR of oral cavity-pharynx and pancreatic cancers was seen. Further prospective follow-up of living members of this cohort, will allow more in-depth analysis of rare cancer sites, latency, and duration of employment, and is warranted.