BACKGROUND & AIMS: In addition to its use for intravenous (I.V.) anesthesia, ketamine can provide pain relief in humans when administered spinally. To elucidate the mechanisms of intrathecal (I.T.) ketamine analgesia, we observed differences in the effects of I.V. and I.T. ketamine on intraspinal evoked potentials (ISEPs) in 28 dogs anesthetized with pentobarbital. Bipolar extradural electrodes were inserted at the cervical and lumbar regions of the spinal cord for recording descending ISEPs represented by the two negative deflections, Waves I and II. I.V. ketamine 2 and 10 mg/ kg did not affect the amplitude and latency of Wave I, whereas the large dose (10 mg/kg) significantly decreased the amplitude but not the latency of Wave II. I.T. ketamine 1 and 5 mg/kg caused significant dose-dependent decreases in both Wave I and II amplitudes and prolongations of both Wave I and II latencies. These I.T. effects on ISEPs are consistent with previous in vitro observations that ketamine blocks axonal conduction. We conclude that axonal conduction block may contribute to the analgesic mechanism of I.T. ketamine.

背景与目标： 除了用于静脉注射 (静脉注射) 麻醉外，氯胺酮还可以减轻脊柱注射时的疼痛。为了阐明鞘内 (I.T.) 氯胺酮镇痛的机制，我们观察了静脉注射和静脉注射氯胺酮对28只用戊巴比妥麻醉的狗的椎管内诱发电位 (ISEPs) 的影响。将双极硬膜外电极插入脊髓的颈椎和腰椎区域，以记录由两个负偏转波I和II表示的下降ISEPs。静脉内氯胺酮2和10 mg/kg不影响第I波的振幅和潜伏期，而大剂量 (10 mg/kg) 显着降低了振幅，但不影响第II波的潜伏期。I.T. 氯胺酮1和5 mg/kg引起I和II波振幅的显着剂量依赖性降低，以及I和II波潜伏期的延长。这些I.T. 对ISEPs的影响与先前的体外观察结果一致，即氯胺酮可阻断轴突传导。我们得出的结论是，轴突传导阻滞可能有助于i.T.氯胺酮的镇痛机制。

BACKGROUND & AIMS: :The time course of ethylene biosynthesis and perception was investigated in ripening peach fruit (Prunus persica) following treatments with the polyamines putrescine (Pu) and spermidine (Sd), and with aminoethoxyvinylglycine (AVG). Fruit treatments were performed in planta. Ethylene production was measured by gas chromatography, and polyamine content by high-performance liquid chromatography; expression analyses were performed by Northern blot or real-time polymerase chain reaction. Differential increases in the endogenous polyamine pool in the epicarp and mesocarp were induced by treatments; in both cases, ethylene production, fruit softening and abscission were greatly inhibited. The rise in 1-aminocyclopropane-1-carboxylate oxidase (PpACO1) mRNA was counteracted and delayed in polyamine-treated fruit, whereas transcript abundance of ethylene receptors PpETR1 (ethylene receptor 1) and PpERS1 (ethylene sensor 1) was enhanced at harvest. Transcript abundance of arginine decarboxylase (ADC) and S-adenosylmethionine decarboxylase (SAMDC) was transiently reduced in both the epicarp and mesocarp. AVG, here taken as a positive control, exerted highly comparable effects to those of Pu and Sd. Thus, in peach fruit, increasing the endogenous polyamine pool in the epicarp or in the mesocarp strongly interfered, both at a biochemical and at a biomolecular level, with the temporal evolution of the ripening syndrome.

背景与目标： : 在用多胺腐胺 (Pu) 和亚精胺 (Sd) 以及氨基乙氧基乙烯基甘氨酸 (AVG) 处理后，研究了成熟桃果实 (Prunus persica) 中乙烯生物合成和感知的时间过程。在植物中进行水果处理。通过气相色谱法测量乙烯产量，通过高效液相色谱法测量多胺含量; 通过Northern印迹或实时聚合酶链反应进行表达分析。处理可诱导外皮和中果皮中内源多胺库的差异增加; 在这两种情况下，乙烯的产生，果实的软化和脱落均受到极大抑制。在多胺处理的水果中，1-氨基环丙烷-1-羧酸氧化酶 (PpACO1) mRNA的上升被抵消并延迟，而乙烯受体PpETR1 (乙烯受体1) 和pper1 (乙烯传感器1) 的转录物丰度在收获时增强。精氨酸脱羧酶 (ADC) 和S-腺苷甲硫氨酸脱羧酶 (SAMDC) 的转录物丰度在表皮和中果皮中均瞬时降低。AVG作为阳性对照，与Pu和Sd具有高度可比的作用。因此，在桃子果实中，在生化和生物分子水平上，内源性多胺库的增加会强烈干扰成熟综合征的时间演变。

BACKGROUND & AIMS: :The intricate problems associated with the delivery and various unnecessary in vivo transitions of proteins and drugs needs to be tackled soon to be able to exploit the myriad of putative therapeutics created by the biotechnology boom. Nanomedicine is one of the most promising applications of nanotechnology in the field of medicine. It has been defined as the monitoring, repair, construction and control of human biological systems at the molecular level using engineered nanodevices and nanostructures. These nanostructured medicines will eventually turn the world of drug delivery upside down. PEGylation (i.e. the attachment of polyethylene glycol to proteins and drugs) is an upcoming methodology for drug development and it has the potential to revolutionise medicine by drastically improving the pharmacokinetic and pharmacodynamic properties of the administered drug. This article provides a total strategy for improving the therapeutic efficacy of various biotechnological products in drug delivery. This article also presents an extensive analysis of most of the PEGylated proteins, peptides and drugs, together with extensive clinical data. Nanomedicines and PEGylation, the latest offshoots of nanotechnology will definitely pave a way in the field of drug delivery where targeted delivery, formulation, in vivo stability and retention are the major challenges.

背景与目标： : 与蛋白质和药物的递送和各种不必要的体内转化相关的复杂问题需要尽快解决，以便能够利用生物技术繁荣带来的无数推定疗法。纳米医学是纳米技术在医学领域最有前途的应用之一。它被定义为使用工程纳米设备和纳米结构在分子水平上监视，修复，构建和控制人类生物系统。这些纳米结构的药物最终将颠覆药物输送的世界。聚乙二醇化 (即聚乙二醇与蛋白质和药物的结合) 是药物开发的一种即将到来的方法，它有可能通过大幅改善所给药药物的药代动力学和药效学特性来彻底改变药物。本文提供了提高各种生物技术产品在药物输送中的治疗效果的总体策略。本文还对大多数聚乙二醇化蛋白，肽和药物进行了广泛的分析，并提供了广泛的临床数据。纳米药物和聚乙二醇化是纳米技术的最新分支，无疑将在药物递送领域铺平道路，其中靶向递送，配方，体内稳定性和保留是主要挑战。

BACKGROUND & AIMS: :Our goal was to identify the role of poly(ADP-ribose) polymerase (PARP) in cerebrovascular dysfunction in Type 1 diabetes mellitus (T1D). In a first series of studies, rats were assigned to nondiabetic and diabetic (streptozotocin; 50 mg/kg IP) groups. Two to three months after injection of streptozotocin, we examine in vivo responses of pial arterioles to nitric oxide synthase (NOS)-dependent (adenosine diphosphate (ADP), acetylcholine and histamine) and -independent (nitroglycerin) agonists. After the initial examination of reactivity to the agonists, we treated pial arterioles acutely with an inhibitor of PARP (PJ-34; 1 microM), and then we again examined responses to the agonists. In a second series of studies, we examine superoxide production (lucigenin chemiluminescence) by parietal cortex tissue in nondiabetic and diabetic rats. We found that dilation of pial arterioles in response to ADP, acetylcholine and histamine, but not to nitroglycerin, was impaired in diabetic compared to nondiabetic rats. In addition, although PJ-34 did not alter responses in nondiabetic rats, PJ-34 alleviated T1D-induced impairment of NOS-dependent vasodilation. We also found that basal production of superoxide was increased in diabetic compared to nondiabetic rats and that PJ-34 decreased this basal production of superoxide. Our findings suggest that T1D impairs NOS-dependent reactivity of cerebral arterioles by a mechanism that appears to be related to the formation of superoxide via activation of PARP.

背景与目标： : 我们的目标是确定聚 (ADP-核糖) 聚合酶 (PARP) 在1型糖尿病 (T1D) 的脑血管功能障碍中的作用。在第一系列研究中，将大鼠分为非糖尿病组和糖尿病组 (链脲佐菌素; 50 mg/kg IP)。注射链脲佐菌素后两到三个月，我们检查了小动脉对一氧化氮合酶 (NOS) 依赖性 (二磷酸腺苷 (ADP)，乙酰胆碱和组胺) 和非依赖性 (硝酸甘油) 激动剂的体内反应。在初步检查对激动剂的反应性之后，我们用PARP抑制剂 (PJ-34; 1 microM) 急性治疗了小动脉，然后我们再次检查了对激动剂的反应。在第二系列研究中，我们检查了非糖尿病和糖尿病大鼠顶叶皮质组织产生的超氧化物 (荧光素化学发光)。我们发现，与非糖尿病大鼠相比，糖尿病大鼠对ADP，乙酰胆碱和组胺 (但对硝酸甘油) 的反应会减弱小动脉的扩张。此外，尽管PJ-34没有改变非糖尿病大鼠的反应，但PJ-34减轻了NOS依赖性血管舒张的T1D-induced损害。我们还发现，与非糖尿病大鼠相比，糖尿病大鼠中超氧化物的基础产量增加，PJ-34降低了超氧化物的基础产量。我们的发现表明，T1D通过一种机制损害了脑小动脉的NOS依赖性反应性，该机制似乎与通过PARP活化形成超氧化物有关。

BACKGROUND & AIMS: :Fractionation of rat L6 myoblast histone H4 mRNA into its three component subspecies revealed that one of the major subspecies (H4-1) contained poly(A). The unique poly(A)+ H4 mRNA makes up about 8% of the total polysomal H4 mRNA population detected. Unlike the poly(A)- histone mRNAs, whose levels are reduced by greater than 95% when myoblasts differentiate into myotubes, the poly(A)+ subspecies is reduced by only 70%. The poly(A)+ H4 mRNA from myotubes incubated with actinomycin D decays with a half-life of 37-42 min, which is similar to that obtained for the poly(A)- H4 mRNAs in myoblasts. Both the poly(A)+ and poly(A)- subspecies decay at an increased rate after inhibition of DNA synthesis. In myoblasts the poly(A)+ H4 mRNA exists almost exclusively in the polysomal compartment (greater than 95%) with little (less than 5%) in the free ribonucleoprotein (mRNA-protein or mRNP) complex compartment of the cell. Poly(A)- histone H4 mRNA subspecies, on the other hand, are distributed with approximately 80% in the polysomal compartment and 20% in the free mRNP complex compartment. The unique poly(A)+ H4 mRNA is unusual, not only in that it contains poly(A) but also in its behavior compared to poly(A)- H4 mRNAs during terminal differentiation.

背景与目标： : 将大鼠L6成肌细胞组蛋白H4 mRNA分离成其三个组成亚种，表明主要亚种 (H4-1) 之一含有poly(A)。独特的poly(A)+ h4mrna构成了检测到的总多体h4mrna群体的约8%。与当成肌细胞分化为肌管时其水平降低大于95% 的聚 (A)-组蛋白mrna不同，聚 (A) 亚种仅降低70%。与放线菌素d孵育的肌管中的poly(A) H4 mRNA衰变，半衰期为37-42分钟，这与在成肌细胞中获得的poly (a)- H4 mRNA相似。在抑制DNA合成后，poly(A) 和聚 (A) 亚种均以增加的速率衰减。在成肌细胞中，poly(A) h4mrna几乎仅存在于多体区室 (大于95%) 中，很少 (小于5%) 存在于细胞的游离核糖核蛋白 (mRNA-蛋白或mRNP) 复合区室中。另一方面，聚 (A)-组蛋白h4mrna亚种在多体区室中分布有大约80%，而在游离的mRNP复合物区室中20%。独特的poly(A) H4 mRNA是不寻常的，不仅因为它包含poly(A)，而且在末端分化过程中与poly(A)- H4 mRNA相比，其行为也是如此。

BACKGROUND & AIMS: :We studied the effects of AVG, ACC, and ethylene on the process of adventitious bud formation in vitro from bulb-scale explants of Lilium speciosum Thunb., cv. Rubrum nr. 10. AVG inhibited plantlet regeneration, especially at non-basal sites. The effects of AVG were counteracted by ACC and TIBA. Ethylene, applied in the first 3 or 7 days of the culture period in a concentration of 1 or 10 ppm, caused an increase in bud number per explant and suppressed the predominantly basipetal polarity of the regeneration sites. Ethylene increased the sensitivity of the tissue to exogenous auxin. A model is proposed showing the influence of ethylene, its biosynthetic pathway, and the other modifying factors on the regulation of plantlet induction in bulb-scale explants by auxin.

背景与目标： : 我们研究了AVG，ACC和乙烯对百合鳞茎鳞茎外植体体外不定芽形成过程的影响。Rubrum nr。10. AVG抑制了植株的再生，尤其是在非基础部位。ACC和TIBA抵消了AVG的影响。在培养的前3或7天以1或10 ppm的浓度施用乙烯，导致每个外植体的芽数增加，并抑制了再生位点的主要基本极性。乙烯增加了组织对外源生长素的敏感性。提出了一个模型，该模型显示了乙烯，其生物合成途径以及其他修饰因素对生长素对鳞茎规模外植体中小植株诱导的影响。

BACKGROUND & AIMS: :Members of the CCAAT/enhancer binding protein (C/EBP) family of transcription factors have been reported to be up-regulated in Alzheimer's disease. In the present study, we have investigated the effects of amyloid-beta (Abeta) peptides on C/EBPbeta and C/EBPdelta, previously shown to be induced by inflammatory stimuli in glial cells. Surprisingly, electrophoretic mobility shift assay showed that both Abeta(1-42) and Abeta(25-35) blocked C/EBP activation induced by the inflammatory cytokine interleukin-1beta (IL-1beta) or lipopolysaccharide (LPS) in mixed primary glial cell cultures from rat. Abeta also blocked IL-1beta- or LPS-induced C/EBP protein levels. The most prominent effects were observed on DNA binding activity and protein levels of C/EBPdelta. Our results demonstrate a dysregulation of C/EBP when glial cells are activated in the presence of Alzheimer Abeta peptides.

背景与目标： : 据报道，转录因子CCAAT/增强子结合蛋白 (C/EBP) 家族的成员在阿尔茨海默氏病中被上调。在本研究中，我们研究了淀粉样 β (Abeta) 肽对C/eppbeta和C/eppdelta的影响，这些蛋白先前被证明是由神经胶质细胞中的炎症刺激诱导的。令人惊讶的是，电泳迁移率变化测定表明，在来自大鼠的混合原代神经胶质细胞培养物中，Abeta(1-42) 和Abeta(25-35) 都阻断了由炎性细胞因子interleukin-1beta (IL-1beta) 或脂多糖 (LPS) 诱导的C/EBP激活。Abeta还阻断IL-1beta或LPS诱导的C/EBP蛋白水平。观察到对C/eppdelta的DNA结合活性和蛋白质水平最显着的影响。我们的结果表明，当存在阿尔茨海默氏病 β 肽时，神经胶质细胞被激活时，C/EBP失调。

BACKGROUND & AIMS: :The 5' cap and 3' poly(A) tail of eukaryotic mRNAs cooperate to synergistically stimulate translation initiation in vivo. We recently described mammalian cytoplasmic extracts which, following ultracentrifugation to partially deplete them of ribosomes and associated initiation factors, reproduce cap-poly(A) synergy in vitro. Using these systems, we demonstrate that synergy requires interaction between the poly(A)-binding protein (PABP) and the eukaryotic initiation factor (eIF) 4F holoenzyme complex, which recognises the 5' cap. Here we further characterise the requirements and constraints of cap-poly(A) synergy in reticulocyte lysates by evaluating the effects of different parameters on synergy. The extent of extract depletion and the amounts of different initiation factors in depleted extracts were examined, as well as the effects of varying the concentrations of KCl, MgCl(2) and programming mRNA and of adding a cap analogue. The results presented demonstrate that maximal cap-poly(A) synergy requires: (i) limiting concentrations of ribosome-associated initiation factors; (ii) precise ratios of mRNA to translation machinery (low concentrations of ribosome-associated initiation factors and low, non-saturating mRNA concentrations); (iii) physiological concentrations of added KCl and MgCl(2). Additionally, we show that the eIF4G-PABP interaction on mRNAs which are capped and polyadenylated significantly increases the affinity of eIF4E for the 5' cap.

背景与目标： : 真核mrna的5' 帽和3' 聚 (A) 尾协同刺激体内翻译起始。我们最近描述了哺乳动物的细胞质提取物，在超速离心以部分耗尽它们的核糖体和相关的起始因子后，它们在体外复制了cap-poly(A) 协同作用。使用这些系统，我们证明协同作用需要聚 (A) 结合蛋白 (PABP) 与真核起始因子 (eIF) 4F全酶复合物之间的相互作用，该复合物识别5' 帽。在这里，我们通过评估不同参数对协同作用的影响，进一步表征了网织红细胞裂解物中cap-poly(A) 协同作用的要求和约束。检查了提取物消耗的程度和消耗的提取物中不同起始因子的量，以及改变KCl，MgCl(2) 和编程mRNA的浓度以及添加cap类似物的影响。提出的结果表明，最大的cap-poly(A) 协同作用需要 :( i) 限制核糖体相关起始因子的浓度; (ii) mRNA与翻译机制的精确比率 (低浓度的核糖体相关起始因子和低的非饱和mRNA浓度); (iii) 添加的KCl和MgCl的生理浓度 (2)。此外，我们显示在被封端和多聚腺苷酸化的mrna上的eIF4G-PABP相互作用显着增加了eIF4E对5' 帽的亲和力。

BACKGROUND & AIMS: :Interferons are used in the therapy of multiple sclerosis, Kaposi's sarcoma, hepatitis and melanoma. Their short half-life that requires frequent injections can be increased by polyethylene glycol (PEG) modification. A 50-year-old patient was diagnosed as having an acrolentiginous melanoma (Breslow >5 mm, Clark level IV) and inguinal lymph node metastases. After surgical excision and lymphadenectomy, immune therapy with 6.0 microg pegylated interferon alpha(2b)/kg body weight, s.c., was started. Cutaneous ulcerations at the injection sites developed 9 months after treatment initiation. The patient also developed blurred vision and presented with binasal scotomas and pathological visually evoked potentials and electroretinogram. The cutaneous ulcerations slowly healed under local therapy and reduction of the concentration of the PEG-modified interferon from 0.86 to 0.43 mg/ml. The dosage was maintained. Two months later, the therapy was stopped due to disease progression. Vision subsequently recovered. Cutaneous reactions evolved at the sites of subcutaneous injections of PEG-modified interferon alpha(2b). Changes in vision can probably be attributed to immunotherapy.

背景与目标： : 干扰素用于治疗多发性硬化症，卡波西氏肉瘤，肝炎和黑色素瘤。需要频繁注射的短半衰期可以通过聚乙二醇 (PEG) 改性来增加。一名50岁的患者被诊断为患有A性黑色素瘤 (Breslow> 5毫米，Clark IV级) 和腹股沟淋巴结转移。在手术切除和淋巴结切除术后，开始使用6.0 microg聚乙二醇化干扰素 α (2b)/kg体重，s.C.进行免疫治疗。治疗开始后9个月，注射部位出现皮肤溃疡。患者还出现了视力模糊，并出现了双耳暗点和病理性视觉诱发电位和视网膜电图。在局部治疗和PEG修饰的干扰素浓度从0.86降低到0.43 mg/ml的情况下，皮肤溃疡缓慢愈合。维持剂量。两个月后，由于疾病进展，治疗停止。视力随后恢复。皮肤反应在皮下注射PEG修饰的干扰素 α (2b) 的部位发生。视力的变化可能归因于免疫疗法。

BACKGROUND & AIMS: :To investigate if the surface modification of intraocular lens (IOL) is efficient in the prevention of posterior capsular opacification (PCO), the acrylic surface of intraocular lens (Acrysof) was polymerized with polyethylene glycol (PEG-IOL). The human lens epithelial cells (1 x 10(4) cells/mL) were inoculated on PEG grafted or unmodified acrylic lenses for the control. The adherent cells on each IOL surface were trypsinized and counted. The every PEG-IOL was implanted in 20 New Zealand rabbits after removal of crystalline lens. The formations of PCO were checked serially through retroilluminated digital photography, and the severity scores were calculated using POCOman. The cell adherence patterns on each IOL were examined by scanning electron microscopy. As a result, the mean number of adherent cells of PEG-IOL (3.2+/-1.1 x 10(3)) tended to be smaller than that of the acrylic controls (3.6+/-1.9 x 10(3)) without a statistical significance (p=0.73). However, the mean severity of PCO formation in PEG-IOL was significantly lower than that in the control during the third to sixth weeks after surgery. Scanning electron microscopy revealed that the more patch-like cells were found firmly attached to the IOL surface in control than in the PEG-IOL. Conclusively, PEG polymerization to the acrylic IOL would possibly lessen the formation of PCO after cataract removal.

背景与目标： : 为了研究人工晶状体 (IOL) 的表面改性是否能有效预防后囊混浊 (PCO)，人工晶状体 (Acrysof) 的丙烯酸表面与聚乙二醇 (PEG-IOL) 聚合。将人晶状体上皮细胞 (1x10(4) 细胞/mL) 接种在PEG移植或未修饰的丙烯酸镜片上，以进行对照。对每个IOL表面的贴壁细胞进行胰蛋白酶处理并计数。去除晶状体后，将每只PEG-IOL植入20只新西兰兔子中。通过逆光数码摄影连续检查PCO的形成，并使用pocomanan计算严重程度评分。通过扫描电子显微镜检查每个IOL上的细胞粘附模式。结果，PEG-IOL的贴壁细胞的平均数目 (3.2 +/-1.1 × 10(3)) 趋向于小于丙烯酸对照的数目 (3.6 +/-1.9 × 10(3))，没有统计学意义 (p = 0.73)。然而，在术后第三至第六周，PEG-IOL中PCO形成的平均严重程度显着低于对照组。扫描电子显微镜显示，与PEG-IOL相比，对照中发现更多的斑块状细胞牢固地附着在IOL表面。最终，聚乙二醇聚合到丙烯酸IOL可能会减少白内障摘除后PCO的形成。

BACKGROUND & AIMS: :Biocompatible and biodegradable pH-responsive hydrogels based on N-vinyl pyrrolidone (NVP), polyethylene glycol diacrylate (PAC) and chitosan were prepared for controlled drug delivery. These interpolymeric hydrogels were synthesized by a free radical polymerization technique using azobisisobutyronitrile (AIBN) as initiator and N,N'-methylenebisacrylamide (BIS) as crosslinker. These hydrogels were subjected to equilibrium swelling studies in enzyme-free simulated gastric and intestinal fluids (SGF and SIF). These swelling studies clearly indicated that these hydrogels were swollen more in SGF when compared to SIF. Theophylline and 5-fluorouracil (5-FU) were entrapped into these hydrogels and equilibrium-swelling studies were carried out for the drug-entrapped gels in enzyme-free SGF and SIF. The in-vitro release profiles of the drugs were established in enzyme-free SGF. More than 50% of the entrapped drugs were released in the first 2 h at gastric pH and the rest of the drug release was slower.

背景与目标： : 制备了基于N-乙烯基吡咯烷酮 (NVP)，聚乙二醇二丙烯酸酯 (PAC) 和壳聚糖的生物相容性和可生物降解的pH响应水凝胶，用于控制药物递送。这些共聚水凝胶是通过自由基聚合技术合成的，使用偶氮二异丁腈 (AIBN) 作为引发剂，N，N'-亚甲基双丙烯酰胺 (BIS) 作为交联剂。这些水凝胶在无酶的模拟胃液和肠液 (SGF和SIF) 中进行了平衡肿胀研究。这些溶胀研究清楚地表明，与SIF相比，这些水凝胶在SGF中的溶胀更多。将茶碱和5-氟尿嘧啶 (5-FU) 包埋到这些水凝胶中，并对无酶SGF和SIF中的药物包埋凝胶进行了平衡溶胀研究。在无酶SGF中建立了药物的体外释放曲线。在胃pH下的前2小时内释放了超过50% 的截留药物，其余的药物释放较慢。

BACKGROUND & AIMS: BACKGROUND AND OBJECTIVES:To minimize acute postoperative pain, a new formulation of slowly released bupivacaine was developed. METHODS:Bupivacaine was microencapsulated at 60% (wt/wt) in poly-lactide-co-glycolide polymers and characterized for physicochemical properties and bupivacaine release kinetics. This formulation was injected around the rat sciatic nerve to produce an antinociceptive effect to toe pinch. Mechanical hyperalgesia following lateral plantar paw incision in rats was assessed for 7 to 14 days when the bupivacaine slow-release formulation was placed at the ipsilateral sciatic nerve and compared with the hyperalgesia that developed with various controls. RESULTS:Bupivacaine was released in vitro at a relatively constant rate over a period of ≈ 72 to 96 hours. Complete antinociception, shown as no response to toe pinch, lasted for 23 ± 7 hours, with a half-recovery time of 42 ± 8 hours after sciatic nerve injection of 0.4 mL of the microspheres delivering 34 mg of bupivacaine. Solutions of 0.5% (wt/vol) bupivacaine-HCl (0.1 mL) produced complete antinociception for less than 2 hours and recovery half-times of 2 hours. Postincisional mechanical hyperalgesia, shown by increased withdrawal responses to von Frey filaments, was absent for 24 hours and was lower than control for 96 hours, when the sciatic nerve was blocked by bupivacaine microspheres, whereas the 0.5% bupivacaine solution reduced postincisional pain for only 4 hours. CONCLUSIONS:Corresponding to its far greater functional blocking time, the microsphere-bupivacaine formulation was able to significantly reduce postoperative pain below control levels for up to 4 days. These findings of several days of postoperative pain relief, for an injectable formulation containing a single active agent, present an improved and potentially promising therapy to prevent acute pain after surgery.

背景与目标：

BACKGROUND & AIMS: :The antisense oligonucleotides are promising agents for application in anti-HIV therapies. The antiretroviral nucleoside analogues administrated into circulatory system are vulnerable to nuclease degradation and require a vehicle which would not only facilitate therapeutic nucleotides into host cells, but would also provide protection against enzymatic degradation. Such potential is exhibited by poly(propylene imine) dendrimers - the branched cationic polymers easily interacting with oligonucleotides to form complexes called "dendriplexes". The aim of the present study was to evaluate the abilities of the fourth generation poly(propylene imine) dendrimers partially modified with maltose (PPI-Mal G4) or maltotriose (PPI-Mal-III G4) to protect anti-HIV antisense oligonucleotides (ODNs) from nucleolytic degradation. The ODNs (AT, GEM91, SREV) were complexed with dendrimers and subjected to cleavage by serum nucleases or endonuclease S1. The results showed that all examined dendrimers protected ODNs against nucleases contained in FBS. Both PPI-Mal G4 and PPI-Mal-III G4 dendrimers completely prevented ODNs digestion by nuclease S1 at neutral pH. The protective capabilities of investigated dendrimers were significantly weaker in acidic environment. The time stability assay showed that the dendriplexes formed by AT, GEM91, SREV and carbohydrate-modified PPI G4 dendrimers still existed after 12h incubation both in low and at neutral pH buffers. The conformational change of dendriplexes in acidic environment was proposed as possible phenomenon leading to exposition of ODNs to nuclease attack and significantly diminishing dendriplexes' resistance to nucleolitic digestion.

背景与目标： : 反义寡核苷酸是有前途的抗HIV疗法药物。循环系统中施用的抗逆转录病毒核苷类似物易受核酸酶降解的影响，并且需要一种载体，该载体不仅将促进治疗性核苷酸进入宿主细胞，而且还将提供针对酶降解的保护。聚 (丙烯亚胺) 树枝状大分子表现出这种潜力-支化的阳离子聚合物很容易与寡核苷酸相互作用以形成称为 “树枝状复合物” 的络合物。本研究的目的是评估用麦芽糖 (PPI-Mal G4) 或麦芽三糖 (PPI-Mal-III G4) 部分修饰的第四代聚 (丙烯亚胺) 树状大分子保护抗HIV反义寡核苷酸的能力 (odn) 从核分解降解。将odn (AT，GEM91，SREV) 与树枝状聚合物复合，并通过血清核酸酶或核酸内切酶s1进行切割。结果表明，所有检查过的树状大分子都保护odn免受FBS中所含核酸酶的侵害。PPI-Mal G4和PPI-Mal-III G4树状大分子都完全阻止了中性pH下核酸酶S1消化ODNs。在酸性环境中，所研究的树状大分子的保护能力明显较弱。时间稳定性测定表明，在低pH和中性pH缓冲液中孵育12小时后，由AT，GEM91，SREV和碳水化合物修饰的PPI G4树状大分子形成的树枝状体仍然存在。提出了在酸性环境中树突状体的构象变化，这是可能导致odn暴露于核酸酶攻击并显着降低树突状体对核仁消化的抵抗力的现象。

BACKGROUND & AIMS: :Many of new chemical discovered in pharmaceutical industry are hydrophobic compounds. Various techniques have been used to overcome solubility problems of hydrophobic drugs in aqueous media. In the meantime, dendrimers have been considered for sustainability, nanoscale size, high carry capacity, tunable terminal functional groups in terms of drug delivery and solubility. In this work, we have synthesized poly(propylene imine) (PPI) dendrimer up to fifth generation using reduction of nitrile groups after Michael addition and also, polyamidoamine (PAMAM) dendrimer up to fourth generation using Michael addition and amidation reactions. fourth and fifth generations of PPI dendrimer and fourth and third generations of PAMAM dendrimer in different concentrations were used to evaluate the solubility of two hydrophobic drugs (tetracycline and dexamethasone). Furthermore, cytotoxicity of dendrimers and dendrimers/drugs hybrids was studied. The results showed that with increasing concentrations and also the generation of dendrimers, the solubility of these two hydrophobic drugs was increased. Cytotoxicity study through MTT assay against Osteoblast-like cell line (MG-63 cells) showed that dendrimers were relatively cytotoxic where adding dexamethasone caused higher cytotoxicity. However, tetracycline showed no significant effect on cytotoxicity whereas prevented cell proliferation.

背景与目标： : 制药工业中发现的许多新化学物质都是疏水性化合物。已使用各种技术来克服疏水性药物在水性介质中的溶解度问题。同时，已经考虑了树枝状聚合物的可持续性，纳米级尺寸，高承载能力，在药物传递和溶解度方面可调的末端官能团。在这项工作中，我们使用迈克尔加成和酰胺化反应后的腈基还原合成了直到第五代的聚 (丙烯亚胺) (PPI) 树枝状大分子，以及使用迈克尔加成和酰胺化反应直到第四代的聚酰胺胺 (PAMAM) 树枝状大分子。使用不同浓度的第四代和第五代PPI树状聚合物以及第四代和第三代PAMAM树状聚合物来评估两种疏水药物 (四环素和地塞米松) 的溶解度。此外，还研究了树状大分子和树状大分子/药物杂种的细胞毒性。结果表明，随着浓度的增加和树枝状聚合物的产生，这两种疏水性药物的溶解度都增加了。通过MTT分析对成骨细胞样细胞系 (MG-63细胞) 的细胞毒性研究表明，在添加地塞米松引起较高细胞毒性的情况下，树枝状聚合物具有相对的细胞毒性。然而，四环素对细胞毒性没有显着影响，而阻止了细胞增殖。

BACKGROUND & AIMS: :Oligonucleotides containing 2'-O,4'-C-ethylene nucleic acids (ENA) have been proven highly effective for antisense therapeutics. 2'-O,4'-C-Ethyleneguanosine and its phosphoramidite were previously obtained from 3,5-di-O-benzy1-4-C-(p-tolulenesulfonyloxyethyl)-1,2-di-O-acetyl-α-D-erythropentofuranose by glycosylation, but with limited efficiency. Using 3,5-di-O-benzy1-4-C-(2-t-butyldiphenylsilyloxyethyl)-1,2-di-O-acetyl-α-D-erythropentofuranose as an alternative substrate, we developed several methods to obtain 2'-O,4'-C-ethyleneguanosine derivatives with much higher yields than previously reported. These methods were also applicable for the synthesis of 2'-O,4'-C-ethyleneadenosine and 2'-O,4'-C-ethylene-5-methyluridine derivatives. Moreover, we investigated the thermodynamic benefit of DNA strands containing 2'-O,4'-C-ethyleneguanosines during duplex formation with complementary RNA. Only a single modification by the nucleoside resulted in a 10-fold greater binding constant of the DNA/RNA duplex.

背景与目标： : 含有2 '-O，4'-C-乙烯核酸 (ENA) 的寡核苷酸已被证明对反义治疗非常有效。2 '-O，4'-C-亚乙基鸟苷及其亚磷酰胺先前是通过糖基化从3,5-二-O-苄基1-4-c-(对甲苯磺酰氧基乙基)-1，2-di-O-acetyl-α-D-erythropentofuranose获得的，但效率有限。使用3,5-二-O-苄基1-4-c-(2-叔丁基二苯基甲硅烷基氧基乙基)-1，2-di-O-acetyl-α-D-erythropentofuranose作为替代底物，我们开发了几种方法来获得2 '-O，4'-C-乙基鸟苷衍生物，其收率远高于以前报道的。这些方法也适用于2 '-O，4'-C-乙烯腺苷和2 '-O，4'-C-ethylene-5-methyluridine衍生物的合成。此外，我们研究了含有2 '-O，4'-C-亚乙基鸟嘌呤的DNA链在互补RNA双链形成过程中的热力学益处。只有核苷的一次修饰才能使DNA/RNA双链体的结合常数提高10倍。