Didanosine (ddI) and zidovudine (ZDV) susceptibilities of human immunodeficiency virus (HIV) isolates from long-term recipients of ddI

Thirty HIV isolates, obtained from 15 patients before and after receiving single drug therapy with didanosine (ddI), were examined for sensitivity to ddI and zidovudine (ZDV) using a peripheral blood mononuclear leukocyte (PBML)-based assay. Fourteen of the patients had ARC, one had AIDS and 12 had received previous therapy with ZDV. After a median of 1 year of ddI therapy, isolates were significantly less sensitive to ddI than were isolates obtained prior to therapy (P = 0.03). A decrease in ddI sensitivity was observed in ten of the 15 isolate pairs. In contrast to ddI susceptibilities, sensitivity to ZDV increased over the same period of time (P = 0.03). Additional isolates were obtained from four patients who received ddI monotherapy for 2 years. Three of these isolates demonstrated no change in ddI sensitivity compared to baseline. No correlation could be made in this study between development of decreased ddI sensitivity and serum p24 levels, CD4 counts, or clinical outcome. Decreased ddI sensitivity occurs frequently among HIV isolates obtained from long-term recipients of ddI. This decreased sensitivity is modest in degree and is of unknown clinical significance.     

TSPO 18 kDa (PBR) Targeted Photosensitizers for Cancer Imaging (PET) and PDT

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Co-delivery of paclitaxel (PTX) and docosahexaenoic acid (DHA) by targeting lipid nanoemulsions for cancer therapy

Breast cancer is one of the most common types of cancer in female patients with high morbidity and mortality. Multi-drug chemotherapy has significant advantages in the treatment of malignant tumors, especially in reducing drug toxicity, increasing drug sensitivity and reducing drug resistance. The objective of this research is to fabricate lipid nanoemulsions (LNs) for the co-delivery of PTX and docosahexaenoic acid (DHA) with folic acid (FA) decorating (PTX/DHA-FA-LNs), and investigate the anti-tumor activity of the PTX/DHA-FA-LNs against breast cancer both in vitro and in vivo. PTX/DHA-FA-LNs showed a steady release of PTX and DHA from the drug delivery system (DDS) without any burst effect. Furthermore, the PTX/DHA-FA-LNs exhibited a dose-dependent cytotoxicity and a higher rate of apoptosis as compared with the other groups in MCF-7 cells. The cellular uptake study revealed that this LNs were more readily uptaken by MCF-7 cells and M2 macrophages in vitro. Additionally, the targeted effect of PTX/DHA-FA-LNs was aided by FA receptor-mediated endocytosis, and its cytotoxicity was proportional to the cellular uptake efficiency. The anti-tumor efficiency results showed that PTX/DHA-FA-LNs significant inhibited tumor volume growth, prolonged survival time, and reduced toxicity when compared with the other groups. These results indicated that DHA increases the sensitivity of tumor cells and tumor-associated macrophages (ATM2) to PTX, and synergistic effects of folate modification in breast cancer treatment, thus PTX/DHA-FA-LNs may be a promising nanocarrier for breast cancer treatment.     

Behavioral effects of (±) 3,4-methylenedioxyamphetamine (MDA) and (±) 3,4-methylenedioxymethamphetamine (MDMA) in the pigeon: interactions with noradrenergic and serotonergic systems

The effects of three amphetamine analogs were assessed in pigeons key pecking under a multiple 3-min fixed-interval (FI), 30 response fixed-ratio (FR) schedule of food presentation. At doses between 0.1 and 10.0 mg/kg, (±) 3,4-methylenedioxyamphetamine (MDA), (±) 3,4-methylenedioxymethamphetamine (MDMA), and (±)-N-ethyl-3,4-methylenedioxyamphetamine (MDE) either had no effect or decreased response rates in both components of the multiple schedule in a dose-dependent manner. MDA was at least 1 log unit more potent than the other two compounds. Metergoline (0.1–1.0 mg/kg), a serotonin (5-HT) antagonist with comparable affinity for the 5-HT₁ and 5-HT₂ receptor subtypes, blocked the rate-decreasing effects of 3.0 mg/kg MDA in both components of the multiple schedule, but did not affect the MDMA dose-response curve. The 5-HT₂ receptor antagonist ketanserin (0.1–3.0 mg/kg) also restored FI and FR responding that was decreased by 3.0 mg/kg MDA, but had no effect on responding suppressed by MDMA. The noradrenergic alpha-1 antagonist prazosin (0.3–3.0 mg/kg) blocked the behavioral effects of 3.0 mg/kg MDMA at doses that did not attenuate MDA's rate-decreasing effects. These results indicate that although MDA and MDMA are structurally similar and have similar behavioral effects, their actions appear to be mediated through different neurotransmitter systems.     

Pharmacokinetics and bioactivity of glial cell line-derived factor (GDNF) and neurturin (NTN) infused into the rat brain

Convection-enhanced delivery (CED) of GDNF and NTN was employed to determine the tissue clearance of these factors from the rat striatum and the response of the dopaminergic system to a single infusion. Two doses of GDNF (15 and 3 μg) and NTN (10 μg and 2 μg) were infused into the rat striatum. Animals were euthanized 3, 7, 14, 21, and 28 days post-infusion. Brains were processed for ELISA, HPLC, and immunohistochemistry (IHC). Both doses of the infused GDNF resulted in a sharp increase in striatal GDNF levels followed by a rapid decrease between day 3 and 7. Interestingly, IHC revealed GDNF in the septum and the base of the brain 14 days after GDNF administration. Dopamine (DA) turnover was significantly increased in a dose-dependent manner for more than 7 days after a single GDNF infusion. NTN persisted in the brain for at least two weeks longer than GDNF. It also had more persistent effects on DA turnover, probably due to its precipitation in the brain at neutral pH after infusion. Our data suggest that daily or continuous dosing may not be necessary for delivering growth factors into the CNS.     

Disposition of intratracheally administered chromium(III) and chromium(VI) in rabbits

Intratracheal instillation of ⁵¹CrCl₃ in anaesthetized rabbits resulted in partial absorption. In blood, the absorbed material was entirely confined to the plasma compartment. Only trace amounts were deposited in liver and kidney. By contrast, after similar application of Na₂⁵¹CrO₄ the bulk of blood radioactivity was present in erythrocytes. Substantial deposition occurred in liver and kidneys. It is concluded that Cr(VI) may enter the body unreduced via the lung and is partly deposited in cells over a prolonged period of time.     

Influences of peripheral adrenocorticotropin 1–39 (ACTH) and human corticotropin releasing hormone (h-CRH) on human auditory evoked potentials (AEP)

Hormones of the hypothalamus-pituitary-adrenal (HPA) axis have been considered to form part of an efferent humoral system modulating central nervous stimulus processing. The present experiments were designed to compare the effects of iv bolus administrations of placebo, porcine ACTH 1–39 (1.5 U) and h-CRH (25 µg) on auditory evoked potentials (AEPs) in healthy men. Also, cardiovascular parameters, cortisol and self-reported mood were assessed. ACTH significantly reduced the amplitude of the N1 component of the AEP; P1 and P2 remained unchanged. The selective reduction of N1 amplitude defies an interpretation of the changes in terms of a reduced stimulus-induced cortical arousal following ACTH; the ACTH-induced changes may rather indicate an influence on frontocortical functions of directing attention. The effect of ACTH on N1 cannot be attributed to its adrenocorticotropic action or to cardiovascular changes, but appears to represent an intrinsic extraadrenal influence of the hormone. The data do not provide evidence for effects of h-CRH on central nervous stimulus processing in humans, after peripheral administration.     

不同表面活性剂修饰的汉防己甲素PLGA纳米粒制备表征及体外评价

目的:基于纳米粒的递送系统,以改善天然化合物汉防己甲素对肺癌的功效。方法:选取聚乙烯醇、普朗尼克-F127和双十二烷基二甲基溴化铵3种不同的稳定剂,采用单乳化扩散溶剂挥发法制备载汉防己甲素的PLGA纳米粒,考察不同稳定剂对载药纳米粒粒径、ζ电位以及对肺癌A549细胞摄取的影响。结果:2%,1%和0.1%浓度的PVA、PF127和DMAB制备的纳米粒呈表面光滑、大小均一的球形,粒径范围均控制在180~200nm;药物包封率为50%~60%;体外释放实验显示,在pH 7.4的PBS溶液中3组载药纳米粒均呈现缓慢持续释药;细胞学实验结果表明3组纳米粒给药系统均表现出比药物更强的抗肿瘤活性。结论:对PLGA进行表面修饰制备的纳米载体能使汉防己甲素的给药效率得到明显提升。     

E-cad和PCNA在膀胱肿瘤中的表达及其意义

目的探讨上皮钙依赖黏附蛋白（E-cad）和增殖细胞核抗原（PCNA）在膀胱肿瘤中的表达及其意义。方法采用免疫组化SP法检测1995～2010年76例膀胱恶性肿瘤和12例良性肿瘤,计算每例切片中癌细胞E-cad的异常表达率及增殖细胞核抗原阳性指数（PLI）。结果 E-cad在76例膀胱恶性肿瘤和12例膀胱良性肿瘤中异常表达率分别为84.2%、16.7%,差异有统计学意义（P〈0.05）。膀胱良、恶性肿瘤中PLI增殖指数分别为（35.85±8.20）%、（80.24±19.52）%,差异有统计学意义（P〈0.05）。两者在膀胱恶性肿瘤中表达呈正相关（P〈0.05）。结论 E-cad与膀胱恶性肿瘤的浸润、转移有关,可作为预测转移潜能的指标,PCNA可作为恶性肿瘤增殖的指标。     

血清脂蛋白(a)水平与脑梗死的关系

目的研究血清脂蛋白（a）水平与脑梗死的关系。方法选取2007年1月～2008年12月在本院神内科住院治疗的100例脑梗死患者作为观察组,选取同时期在体检中心进行健康体检的100例健康成人作为对照组,对两组受试者分别检测LP（a）的水平,观察LP（a）水平与缺血性脑血管疾病的关系。结果观察死组血清LP（a）水平显著高于对照组（P〈0.05）;观察组的各种亚型中,大、中面积的脑梗死组血清LP（a）水平显著高于对照组（P〈0.05）,腔梗组和对照组比较差异无统计学意义（P〈0.05）。脑梗死组的前后循环亚组血清LP（a）水平显著高于对照组（P〈0.05）,前后循环亚组之间差异无统计学意义（P〈0.05）。Logistic回归分析显示：血清LP（a）水平与脑梗死的发生有一定的相关性。结论血清LP（a）水平升高可能是缺血性脑卒中的重要危险因素之一,主要和脑部大、中动脉梗死相关,和腔隙性梗死无明显相关性。     

Pharmacological characterization of a selective COX-2 inhibitor MF-tricyclic, [3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone], in multiple preclinical species

Selective type 2 cyclooxygenase (COX-2) inhibitors are often used in preclinical studies without potency and selectivity data in the experimental species. To address this issue, we assessed a selective COX-2 inhibitor MF-tricyclic in four commonly used species, namely mice, rats, guinea pigs and rabbits, in the present study. In both the guinea pig and rabbit whole blood assay, the compound inhibited lipopolysaccharide (LPS)-induced PGE₂ production with an IC₅₀ (COX-2) of 0.6 and 2.8 μM, respectively. By comparison, the compound displayed a much weaker activity on clot-induced formation of thromboxane with an IC₅₀ (COX-1) of > 10 μM (guinea pigs) and 23 μM (rabbits). In keeping with the in vitro potency data, the compound significantly inhibited interleukin-1 beta (IL-1β) -induced PGE₂ formation in the rabbit synovium at plasma concentrations near the whole blood assay IC₅₀ for COX-2 but much lower than that for COX-1. MF-tricyclic was also potent and selective toward COX-2 in mice, inhibiting carrageenan-induced PGE₂ accumulation in the air pouch dose-dependently (ED₅₀ = 0.5 mg/kg) without affecting stomach PGE₂ levels. In rats, MF-tricyclic was found to be effective in three standard in vivo assays utilized for assessing COX-2 inhibitors, namely, LPS-induced pyresis, carrageenan-induced paw edema and adjuvant-induced arthritis at the doses that did not inhibit stomach PGE₂ levels. Similar to that in rats, the compound displayed pharmacological efficacy in mice, guinea pigs and rabbits when tested in the LPS pyresis model. Our data reveal that MF-tricyclic has the desired biochemical and pharmacological properties for selective COX-2 inhibition in all four test species.     

Freeze-Drying and Lyopreservation of Diblock and Triblock Poly(Lactic Acid)–Poly(Ethylene Oxide) (PLA–PEO) Copolymer Nanoparticles

In this study, the formulation and process parameters that determine successful production and long-term stability of freeze-dried poly(lactic acid) (PLA) nanoparticles with “hairy-like” poly(ethylene oxide) (PEO) surfaces were investigated. Nanoparticles with grafted (covalently bound) PEO coatings were produced by the salting-out method from blends of PLA and PLA–PEO diblock or triblock copolymers. PLA nanoparticles with physically adsorbed PEO were also produced. The redispersibility of the nanoparticles after freeze-drying under various conditions was assessed. The surface of the nanoparticles was characterized and classified in terms of “brush” and “loop” conformations. Upon freeze-drying, it appeared that the presence of PEO at the nanoparticle surface could severely impair the redispersibility of the particles, especially in the PEO-grafted systems. This effect was shown to be related to the amount and molecular weight of PEO in the various formulations. In most cases, particle aggregation was prevented by use of trehalose as lyoprotective agent. Increasing the concentration of particles in the suspension to be freeze-dried was shown to induce much less damage to the nanoparticles, and freezing the suspension at a very low temperature (?196°C) was found to further improve the lyoprotective effect. Most of the lyoprotected nanoparticles remained stable for at least 12 weeks at 4 and ?25°C. The production and preservation of freeze-dried PLA–PEO diblock and triblock copolymer nanoparticles is feasible under optimized lyoprotective conditions.     

A physiologically based model for the ingestion of chromium(III) and chromium(VI) by humans.

A physiologically based model of human chromium kinetics has been developed, based on an existing physiologically based model of human body and bone growth (O'Flaherty, 1993, Toxicol. Appl. Pharmacol. 118, 16-29; 1995a, Toxicol. Appl. Pharmacol. 131, 297-308; 2000, Toxicol. Sci. 55, 171-18) and an existing physiologically based model of chromium kinetics in rats (O'Flaherty, 1996, Toxicol. Appl. Pharmacol. 138, 54-64). Key features of the adapted model, specific to chromium, include differential absorption of Cr(VI) and Cr(III), rapid reduction of Cr(VI) to Cr(III) in all body fluids and tissues, modest incorporation of chromium into bone, and concentration-dependent urinary clearance consistent with parallel renal processes that conserve chromium efficiently at ambient exposure levels. The model does not include a physiologic lung compartment, but it can be used to estimate an upper limit on pulmonary absorption of inhaled chromium. The model was calibrated against blood and urine chromium concentration data from a group of controlled studies in which adult human volunteers drank solutions generally containing up to 10 mg/day of soluble inorganic salts of either Cr(III) (chromic chloride, CrCl(3)) or Cr(VI) (potassium dichromate, K(2)Cr(2)O(7)) (Finley et al., 1997, Toxicol. Appl. Pharmacol. 142, 151-159; Kerger et al., 1996, Toxicol. Appl. Pharmacol. 141, 145-158; Paustenbach et al., 1996, J. Toxicol. Environ. Health 49, 453-461). In one of the studies, in which the chromium was ingested in orange juice, urinary clearance was observed to be more rapid than when inorganic chromium was ingested. Chromium kinetics were shown not to be dependent on the oxidation state of the administered chromium except in respect to the amount absorbed at these ambient and moderate-to-high exposures. The fraction absorbed from administered Cr(VI) compounds was highly variable and was presumably strongly dependent on the degree of reduction in the gastrointestinal tract, that is, on the amount and nature of the stomach contents at the time of Cr(VI) ingestion. The physiologically based model is applicable to both single-dose oral studies and chronic oral exposure, in that it adequately reproduced the time dependence of blood plasma concentrations and rates of urinary chromium excretion in one of the subjects who, in a separate experiment, ingested daily 4 mg of an inorganic Cr(VI) salt in 5 subdivided doses of 0.8 mg each for a total of 17 days. The high degree of variability of fractional absorption of Cr(VI) from the gastrointestinal tract leads to uncertainty in the assignment of a meaningful value to this parameter as applied to single Cr(VI) doses. To model chronic oral chromium exposure at ambient or moderately above-ambient levels, the physiologically based model in its present form should be usable with urinary clearance set to a constant value of 1-2 liters/day and the gastrointestinal absorption rate constants set at 0.25/day for Cr(III) and 2.5/day for Cr(VI). The model code is given in full in the Appendix.     

The Effects of Etimicin and Gentamicin on Renal Endoplasmic Reticulum ~(45)Ca~(2 )-Uptake and Ca~(2 )-Mg~(2 )-ATPase Activity

目的：研究爱大霉素和庆大霉素对大鼠肾皮质内质网４５Ｃａ２＋摄取以及对内质网膜上Ｃａ２＋Ｍｇ２＋ＡＴＰａｓｅ活性的影响。方法：４５Ｃａ２＋示踪技术和孔雀蓝分光光度法。结果：爱大霉素和庆大霉素在大于或等于３．４×１０４ｍｏｌ·Ｌ１时，能抑制内质网４５Ｃａ２＋摄取（抑制率分别大于或等于１７．４％和２５．５％）；在３．４×１０２ｍｏｌ·Ｌ１时，对内质网膜上Ｃａ２＋Ｍｇ２＋ＡＴＰａｓｅ活性有抑制作用（抑制率分别为２４．１７％和２９．１９％）。结论：爱大霉素和庆大霉素在较高浓度时可使胞浆钙升高，这可能与其产生肾毒性有关     

油茶皂苷抗心肌缺血大鼠氧自由基和脂质过氧化作用

目的　以皮下注射异丙肾上腺素 (ISO)诱发大鼠心肌损伤为模型 ,观察油茶皂苷 (SQS)对心肌线粒体MDA含量、SOD、GSH Px活性的影响。方法　实验分生理盐水组 (NS组 )、ISO诱发损伤组 (I/R组 )、SQSⅠ组 (I/R +SQS 0 1mg·kg-1)和SQSⅡ组 (I/R +SQS 0 2mg·kg-1)。从阴茎静脉注射各被试药物或NS ,每天 1次 ,连续 3d。末次给药后取心肌组织行上述指标的测定。结果　I/R组MDA含量明显升高、SOD及GSH Px活性显著降低 ;SQS能对抗ISO所致上述指标的改变 ,且呈剂量依赖关系。结论　SQS具有抗ISO所致大鼠心肌缺血时氧自由基和脂质过氧化作用     

Phase I study of paclitaxel (taxol) and granulocyte colony stimulating factor (G-CSF) in patients with unresectable malignancy

A phase I trial of a 24-hour infusion of paclitaxel was conducted to identify the maximum tolerated dose of paclitaxel with granulocyte colony-stimulating factor (G-CSF) in patients with unresectable malignancy previously untreated with chemotherapy. Nineteen patients with metastatic melanoma or non-small cell lung cancer were treated with paclitaxel administered at 250, 300, 400 mg/m² every 3 weeks. G-CSF, 5 µg/kg was given as a daily subcutaneous injection 24 hours after the completion of the infusion. Dose limiting myelosuppression and peripheral neuropathy was observed at 400 mg/m² and 350 mg/m². Paclitaxel can be safely administered as a 24-hour infusion at 300 mg/m² with G-CSF. Further studies of paclitaxel and G-CSF are recommended to determine a dose–response relationship in sensitive tumors.     

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

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Effects of simvastatin and carnitine versus simvastatin on lipoprotein(a) and apoprotein(a) in type 2 diabetes mellitus

Aim: The aim of the present study was to compare the effects of simvastatin and L-carnitine coadministration versus simvastatin monotherapy on lipid profile, lipoprotein(a) (Lp(a)) and apoprotein(a) (Apo(a)) levels in type II diabetic patients. Patients/methods: In this double-blind, randomized clinical trial, 75 patients were assigned to one of two treatment groups for 4 months. Group A received simvastatin monotherapy; group B received L-carnitine and simvastatin. The following variables were assessed at baseline, after washout and at 1, 2, 3 and 4 months of treatment: body mass index, fasting plasma glucose, glycated hemoglobin, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, Apolipoprotein A1, Apo B, lipoprotein(a) and apoprotein(a). Results: At the end of treatment in the carnitine and simvastatin combined group compared with the simvastatin alone group, we observed a significant decrease in glycemia (p < 0.001), tryglicerides (p < 0.001), Apo B (p < 0.05), Lp(a) (p < 0.05), apo(a) (p < 0.05), while HDL significantly increased (p < 0.05). Conclusions: The coadministration of carnitine and simvastatin resulted in a significant reduction in Lp(a) and apo(a) and may represent a new therapeutic option in reducing plasma Lp(a) levels, LDL cholesterol and Apo B100.     

102例药物致中枢神经系统不良反应分析

目的了解引起中枢神经系统不良反应的药物及相关因素。方法收集两院上报的不良反应病例598例，筛选出中枢神经系统不良反应病例102例，用SPSS8．0进行分析。结果不良反应的发生与药物的剂量、给药途径、合并用药有关．老年人和儿童是易感人群。结论抗感染药物是引起中枢神经系统不良反应主要药物．其次是中枢神经系统药物。     

Purification and characterization of rabbit muscle acylphosphatase in the thiol (-SH) form

Modifications in the muscle acylphosphatase purification procedure enabled us to isolate the enzyme with its sole cysteine in the -SH form; this enzyme form is the most abundant in vivo. Our data demonstrate that the enzyme forms purified by previously reported procedures can be easily derived from a reaction of the SH-enzyme with oxidized glutathione. Probably most, or even all, of these enzyme forms are artifacts due to the purification. The SH-acylphosphatase shows kinetic parameters similar to those reported for the mixed disulfide with glutathione and S-S dimer, except for the specific activity value, which is about twice as much, and the Km, which is reduced.