肝靶向抗病毒药Lac-PLL-ACV的制备及其趋肝性研究

目的：减少抗病毒药阿昔洛韦（Acyclovir,ACV）在治疗乙型肝炎中的肝外毒副作用，获得肝靶向ACV偶联物。方法：多聚赖氨酸（Poly-L-lysine,PLL)在氰硼酸钠的催化作用下与乳糖反应生成乳糖化多聚赖氨酸，乳糖化多聚赖氨酸与咪唑化阿昔洛韦在37℃pH9.5的条件下反应合成偶联物乳糖化多聚赖氨酸－阿昔洛韦（Lactosaminated poly-L-lysine-acyclovir,Lac-PLL-ACV）。偶联物经尾静脉注射进入小鼠体内后，收集小鼠血浆及肝脏样品，用高效液相色谱法测定药物浓度，研究遇联物的体内分布和药代动力学。结果：HPLC检测证实Lac-PLL-ACV在血浆中十分稳定，不易解离出ACV。偶联物的肝最大摄取率约为60％，是ACV组的10倍以上，偶联物肝中的T1／2，AUC，CL分别为ACV的4．2倍，56．6倍和1／57，具有明显的肝靶向性。结论：乳糖化多聚赖氨酸作为肝去唾液酸糖蛋白受体（Asialoglycoprotein receptor,ASGPR)介导的一种药物载体，能使抗病毒药ACV获得较满意的肝靶向性。     

慢性乙型肝炎中可溶性白细胞介素2受体与其它血清学指标的关系

目的 :探讨血清可溶性白细胞介素 2受体 (sIL 2R)在慢性乙型病毒性肝炎 (慢乙肝 )中的发病机制及sIL 2R与肝纤维化指标、肝功能的相关关系。方法 :对 312例肝活检病人按组织病理学炎症和纤维化程度进行分级分期 ,同时检测了病人血清sIL 2R、肝功能及肝纤维化相关指标。结果 :血清sIL 2R均值较对照组明显增高 (P <0 .0 1) ,增幅随着肝脏病理炎症和纤维化程度的加重而逐渐加大 ,各组间比较差异有显著性 (P <0 .0 5或P <0 .0 1)。sIL 2R与血清白蛋白 (A)呈显著负相关 ,与血清脯氨酸肽酶 (PLD)、Ⅳ型胶原 (CⅣ )、层粘连蛋白 (LN)、透明质酸 (HA)、Ⅲ型前胶原氨基端肽 (PⅢNP)、肝功指标中的TB、DB、G、ALT、AST、AKP、γ GT呈显著正相关 (P <0 .0 5或P <0 .0 1)。结论 :慢乙肝病人血清sIL 2R水平与A呈显著负相关 ,与PLD、CⅣ、LN、HA、PⅢNP呈显著正相关 ;sIL 2R的血清水平能反映肝脏组织学病变的程度 ,可作为判断肝组织炎症和纤维化程度的参考指标。     

慢传输性便秘结肠阿片受体的病理生理改变

目的探讨慢传输性便秘(STC)的发病机制和病理生理改变。方法应用放射配体结合分析法,检测患者结肠mu、kappa阿片受体,观察其含量变化。结果STC患者结肠mu阿片受体的最大结合数(Bmax)和解离常数(KD)比正常对照组明显增加(Bmax400.950比96.304pmol,KD431.314比179.839pmol);kappa阿片受体含量检测亦有类似结果(Bmax:375.073比45.264pmol,KD485.407比141.016pmol)。结论STC患者阿片受体含量增加,内源性阿片肽活性增加。提示采用阿片受体拮抗剂可能是治疗STC的一个新途径。     

儿童慢性乙型肝炎细胞免疫功能及胸腺素疗效

目的　探讨慢性乙型肝炎(CHB)患儿细胞免疫功能及胸腺素疗效。方法　6 0例CHB患儿随机分为常规组(予常规治疗)和胸腺素组(在常规治疗基础上+胸腺素) ,并以6 0例健康儿童作为正常对照组。于治疗前、疗程结束后1mo检测T细胞亚群(CD+ 3 、CD+ 4 、CD+ 8)、血清白细胞介素2 (IL 2 )及可溶性白细胞介素2受体(sIL 2R)水平;定期复查肝功能、乙肝标志物和HBV DNA。结果　与正常对照组比较,CHB组CD+ 3 与CD+ 4 的百分率、CD+ 4 /CD+ 8及血清IL 2水平明显降低(P均<0 0 1) ,CD+ 8百分率及血清sIL 2R水平明显升高(P均<0 0 1) ;与常规组比较,胸腺素组血清ALT明显下降(P <0 0 1) ,ALT复常时间明显缩短(P <0 0 1) ,HBeAg转阴率明显上升(P <0 0 5 ) ,各免疫学指标明显恢复,差异均有统计学意义(P <0 0 1或P <0 0 5 )。结论　CHB患儿细胞免疫功能低下,胸腺素能增强细胞免疫功能,有利于病毒清除和肝功能的恢复     

儿童髓母细胞瘤中VEGFR-2的表达

目的：探讨血管内皮生长因子受体VEGFR－2在儿童髓母细胞瘤中的表达及临床意义。方法：采用免疫组化LSAB法检测84例获随访的儿童髓母细胞瘤中的VEGFR－2表达，按术后生存期3，5，10年分为A，B，C三组，使用Cox回归统计分析。结果：84例儿童髓母细胞瘤中，VEGFR－2阳性表达74例（88．09％），A，B，C三组间VEGFR－2阳性表达分别为100％，88．89％，55．33％（P＜0．01），Cox回归分析显示VEGFR－2是影响生存时间的一个独立的预后因子，它与预后存在负相关关系。结论：VEGFR－2表达水平可作为儿童髓母细胞瘤的预后指标之一。     

Chronic treatment with scopolamine and physostigmine changes nerve growth factor (NGF) receptor density and NGF content in rat brain

Nerve growth factor (NGF) and NGF receptors were measured in cortex and hippocampus of rats treated with drugs affecting cholinergic neurotransmission. High (K_d= 0.045nM) and low (K_d= 21nM) affinity¹²⁵I-NGF binding sites were present in both cortical and hippocampal membranes with hippocampus containing higher numbers of both sites than cortex. Chronic treatment of rats with the muscarinic receptor antagonist scopolamine (5 mg/kg, twice daily) decreased the density of high- and low-affinity sites by 50–90% in cortical and hippocampal membranes. These changes were seen after 7 days, but not 3 days, of scopolamine treatment. Chronic infusion of physostigmine (1 mg/kg/day) using minipumps increased the number of high- and low-affinity sites in cortex 3- and 6-fold, respectively. The changes in receptor-binding parameters induced by physostigmine were transient as they were evident after 3 days of treatment, but returned to control levels after 7 days. NGF content in cortex and hippocampus was reduced by about 50% following 7, but not 3, days of chronic physostigmine infusion. In contrast, scopolamine treatment failed to change NGF levels in the cholinergic neuronal target regions but it decreased NGF content in the septal area. The content of NGF mRNA in the cortex measured by Northern blot analysis failed to change following either scopolamine or physostigmine treatment. The results suggest that levels of NGF and NGF receptors in the target regions of cholinergic neurons are regulated by the extent of cholinergic neurotransmitter activity.     

Baclofen-induced disinhibition in area CA1 of rat hippocampus is resistant to extracellular Ba

The mechanism of disinhibition produced by (±)-baclofen was studied using intracellular recording in area CA1 of rat hippocampal slices. Baclofen reversibly depressed monosynaptic IPSPs evoked by direct activation of interneurons in the presence of the excitatory amino acid receptor antagonists 6,7-dinitroquinoxaline-2,3-dione (DNQX) andd,l-2amino-5-phosphonovalerate (APV). Ba²⁺ prevented baclofen-induced hyperpolarization of pyramidal neurons but not depression of monosynaptic IPSPs by baclofen. Baclofen reversibly depressed monosynaptic IPSPs when applied close to the recording site, but was ineffective when applied close to the stimulating site in stratum radiatum. These results suggest that baclofen disinhibits pyramidal neurons in area CA1 of the rat hippocampus by activating receptors on the terminals of inhibitory neurons that are coupled to a Ba²⁺-insensitive effector mechanism.