Generalized pharmacokinetic modeling for drugs with nonlinear binding: I. Theoretical framework

The following integrodifferential equation is proposed as the basis for a generalized treatment of pharmacokinetic systems in which nonlinear binding occurs $$\phi '(c_u )c'_u = - q(c_u ) + g*c_u + f$$ where c_u≡unbound plasma drug concentration, f≡drug input rate,'indicates the derivative of a function, and * indicates the convolution operation: (g* c_u)(t)=∫ ₀ ^t g(t?u)c_udu.Possible physical interpretations of the functions q, g and f are: q (c_u)≡ rate at which drug leaves the sampling compartment, g * c_u ≡ rate at which drug returns to the sampling compartment from the peripheral system (tissues that are kinetically distinct from the sampling compartment), and φ(c_u) ≡ amount of drug in the sampling compartment. The approach assumes that drug binding is sufficiently rapid that it may be treated as an equilibrium process. It may be applied to systems in which nonlinear binding occurs within the sampling compartment, i.e., in the systemic circulation or in tissues to which drug is rapidly distributed. The proposed relationship is a generalization of most existing models for drugs with nonlinear binding. It can serve as a general theoretical framework for such models or as the basis for “model-independent” methods for analyzing the pharmacokinetics of drugs with nonlinear binding. Computer programs for the numerical solution of the integrodifferential equation are presented. Methods for pharmacokinetic system characterization, prediction and bioavailability are presented and demonstrated.     

Natural killer activity and serum immunosuppressive acidic protein levels in esophageal and gastric cancers

The natural killer (NK) activity of peripheral blood mononuclear cells and serum immunosuppressive acidic protein (IAP) levels were examined in patients with esophageal or gastric cancer, before and after surgery. Patients with stage IV esophageal or stage IV gastric cancer had significantly lower NK activity (39.5±14.8% and 37±11.6%, respectively), and also higher serum IAP levels (778±264 g/mL and 633±156 g/mL, respectively), than the corresponding control values (50±5.6% and 375±26 g/mL, respectively). Patients with esophageal or gastric cancer who underwent curative resection had high NK activity (54.8±11.6% and 54.8±8.0%, respectively), and low IAP levels (471±116 g/mL and 490±42 g/mL, respectively), compared with those who underwent non-curative resection. Patients who underwent non-curative resection had lower NK activity and higher serum IAP levels than those who underwent curative resection, even 1 month after surgery. Mononuclear cells in the regional lymph nodes and tumor specimens showed significantly lower NK activity than those in the peripheral blood and spleen. Thus, NK activity and the IAP level reflected the immunocompetence, clinical course, and surgical curability of those patients. NK cells appeared not to have any significant antitumor activity in the regional lymph nodes or in the tumor itself, although they were still active in the peripheral blood.     

阉割和睾酮替代对大鼠应激免疫抑制蛋白的影响

目的 :研究阉割和睾酮替代对束缚应激模型大鼠血清中应激免疫抑制蛋白的影响。方法 :成年雄性SD大鼠随机分为正常对照组、假手术组、阉割组、阉割后睾酮替代组。每组 10～ 12只。以上各组随机抽出一半给予束缚应激 ,另一半作为不应激对照。观察各组大鼠血清对ConA诱导的淋巴细胞转化的作用 ,作为反映血清中应激免疫抑制蛋白含量的指标。在离体实验中观察不同浓度的睾酮对淋巴细胞转化的直接作用。结果 :阉割可促进应激大鼠血清中应激免疫抑制蛋白的产生 ,睾酮替代可对抗这一作用。结论 :睾酮可在一定范围内对抗应激免疫抑制蛋白的产生。     

P~(53)蛋白在口腔扁平苔藓癌变诊断中的意义

目的 :探索口腔粘膜扁平苔藓 (OLP) P53蛋白的表达及其在癌变诊断中的应用价值。方法 :采用 S- P免疫组化方法 ,观察在 2 5例 OLP、2 0例鳞癌 (OSCC)中 P53蛋白的表达。结果 :1 P53蛋白的阳性表达在 OLP早期已出现 ,各组间 P53阳性表达率间有显著性差异。2在 OSCC中其阳性表达率高达 80 % ,随着细胞异常增生程度的增高而增高。结论 :1在 OSCC的形成过程中 ,抑癌基因 P53的失活可能参与调节作用 ;2 P53蛋白作为判断 OLP癌变的辅助性参考指标 ,具有一定的可行性     

喉癌下咽癌TGFβ1、p16表达的意义

目的 :通过对喉癌、下咽癌组织中转化生长因子 β1(TGFβ1)及 p16蛋白的定位、半定量研究 ,探讨其在喉癌、下咽癌组织中的表达与意义。方法 :采用SABC免疫组化法研究TGFβ1与 p16蛋白的表达 ,并对表达结果进行统计分析。结果 :TGFβ1位于胞浆 /胞膜 ,p16蛋白位于胞浆 /胞核。TGFβ1强表达率为61% ,p16蛋白强表达率为 66%。高分化与中、低分化肿瘤的TGFβ1表达均有统计学差异 (P <0 .0 5) ;高分化与低分化肿瘤的 p16蛋白表达具统计学差异 (P <0 .0 5)。TGFβ1和 p16蛋白之间存在正相关系 (P <0 .0 5)。TGFβ1和 p16蛋白的表达与患者年龄、性别、肿瘤生长部位、病程、临床分期无明显相关。 结论 :TGFβ1与 p16蛋白在喉癌、下咽癌中存在缺失表达 ,在高分化肿瘤中有更高的表达 ,在细胞周期中具有共同的作用。     

蛋白酪氨酸磷酸酶H 型受体的生物学功能及其在肿瘤中的研究进展

蛋白酪氨酸磷酸酶H型受体(protein tyrosine phosphatase H receptor,PTPRH)基因是一种编码胃癌相关蛋 白的基因,通过翻译后COOH-末端区域的酪氨酸磷酸化修饰发挥其生物学功能。PTPRH在多种肿瘤中呈异常表达, 其生物学功能与肿瘤的发生、发展及预后密切相关。     

变应性鼻炎与气道高反应的关系

目的 :探讨变应性鼻炎与气道高反应性的相关性。方法 :用 1∶ 1 0 0 ( w/v)蒿属花粉对 50例变应性鼻炎和 2 0例正常者做支气管激发试验 ,分别测定两组第 1秒用力呼气量 ( FEV1) ;测血清中嗜酸性粒细胞阳离子蛋白 ( ECP)。结果 :支气管激发试验前 ,两组支气管均无症状 ,鼻炎组FEV1为 ( 70± 2 0 ) % ,对照组为 ( 85.6± 8.9) % ,两组有显著性差异 ( P <0 .0 1 ) ;支气管激发后 ,鼻炎组中 2 3例胸部有紧迫感 ,1 0例有哮鸣 ,5例有喘息 ,1 2例无症状 ,激发阳性率为 76%。对照组均无支气管症状。激发后鼻炎组 FEV1为 ( 60± 2 0 ) % ,对照组为 ( 85.6± 8.9) % ,两组有显著性差异 ( P <0 .0 5)。鼻炎组 ECP为 ( 30 .37± 1 8.92 ) μg/L,对照组为 ( 5.2 4± 3.2 3) μg/L,两组有显著性差异 ( P <0 .0 5)。结论 :变应性鼻炎不仅鼻粘膜有变态反应所致的慢性炎症 ,而且大部分气道也有慢性炎症反应而导致气道高反应性。     

胆汁泡蛋白ELISA检测法的建立与初步临床应用

目的 建立胆汁泡蛋白快速检测法,筛选有效的胆石症防治手段。方法 获取３３．５ｋｄ胆汁泡蛋白,通过微量抗原免疫法获得高效价抗体,建立ＥＬＩＳＡ标准曲线;并应用ＥＬＩＳＡ法测定正常人、胆石症患者胆汁和血清中泡蛋白含量,同时观察不同溶石防药和利胆冲剂、胆酸钠等对泡蛋白的影响。结果 建立了ＥＬＩＳＡ标准曲线,其曲线方程为Ｙ＝０．０３５Ｘ（ｒ＝０．９９）;正常人胆汁和血清中３３．５ｋｄ泡蛋白含量都明显较胆固     

基因芯片对PMA激活的血管内皮细胞早期反应基因的研究

目的 :用基因芯片研究 PMA激活的血管内皮细胞的早期反应基因 (imm ediate early response gene,ERG)。方法 :以包含 40 96条人类基因的 DNA芯片检测血管内皮细胞受代谢增强剂 PMA(phorbol myristate acetate)激活后早期的基因表达谱 ,并从中筛查出 ERG。结果 :血管内皮细胞受 PMA作用 6 h后 ,17条基因上调 ,11条下调。数据处理聚类分析表明 17条上调基因中多数 (13/ 17)属蛋白质磷酸酶和转录调控因子基因 ,而下调基因中多数 (9/ 11)为细胞分裂相关基因。结论 :证明PMA激活的人血管内皮细胞早期反应基因主要是转录调控因子和蛋白质磷酸酶基因。     

YAG激光治疗牙本质过敏症的疗效分析

目的 :为探索治疗牙本质过敏症的新疗法 ,观察激光治疗后过敏齿的临床疗效 .方法 :应用 Nd:YAG激光点射治疗过敏齿 152 1颗 ,其中 °过敏 10 17颗 , °过敏 50 4颗 .结果 :即刻有效率为98.6 8% ;经 3～ 12个月的临床观察 , °过敏痊愈 814颗 (80 .0 4 % ) ,显效 183颗 (17.99% ) ,有效率为98.0 3% ; °过敏痊愈 119颗 (2 3.6 1% ) ,显效 339颗 (6 7.2 6 % ) .结论 :两组总有效率为 95.6 6 %。操作简便 ,无痛苦 ,是一种快速有效的方法