7-溴化乙氧苯四氢巴马汀抗心律失常作用的机理

7-溴化乙氧苯四氢巴马汀(7-bromoethoxybenzene-tetrahydropalmatine,EBP)10及30μmol/L均能明显延长豚鼠乳头状肌动作电位时程(APD),但对动作电位幅度(APA),静息电位(RP),超射(OS),零期最大上升速率(V_max)无显著影响。EBP能按剂量抑制犬浦氏纤维慢内向电流(I_si)及钾外向电流(I_x)的峰值。     

Ultrasonographic Risk Score of Carotid Plaques

OBJECTIVE: to determine the relative significance of ultrasonographic parameters of carotid plaques to develop an Activity Index (AI) which could correlate with clinical findings. METHOD: two hundred and fifteen plaques in 141 patients underwent ultrasonography and computer-assisted structural analysis. In half the patients (group 1), plaques were classified as either homogeneous and heterogeneous and ultrasonographic appearances related symptomatic (SP) or asymptomatic (AP) station. The probability of SP for each ultrasound parameter was used to define an Activity Index (AI). The AI was then applied the second half of patients (Group 2) to assess the value of AI in determining symptomatic station. RESULTS: the parameters with highest morbility were surface disruption, severe stenosis and low grey scale median and, additionally in heterogenous plaques heterogeneity and the presence of a juxta-luminal echolucent area. The power in group 2 of AI to identify symptomatic plaques was determined. Mean AI was for SP-75 (41-100) and for AP-43 (22-100); 78% of SP have AI>60 and 70% of AP have AI<50. The cut-off point between the two groups was 52. ROC curve analysis of the AI were obtained to determine its diagnostic accuracy. CONCLUSION: Activity Index is an objective parameter of plaque echostructure that positively correlates with symptoms. AI may contribute to better selection for treatment of patients with carotid artery disease.     

Design, synthesis, and properties of (4S)-7-(4-amino-2-substituted-pyrrolidin-1-yl)quinolone-3-carboxylic acids

The quinolonecarboxylic acids constitute a class of extremely potent and orally active broad-spectrum antibacterial agents. These compounds have been shown to inhibit DNA gyrase, a key enzyme in bacterial DNA replication. The 7-(3-aminopyrrolidinyl)quinolone A-60969 (1) is a particularly potent member of this class and is currently undergoing clinical evaluation. We have studied a series of enantiomerically homogeneous (4S)-7-(4-amino-2-substituted-pyrrolidinyl)quinolones in an effort to utilize the 2-position of the pyrrolidine moiety to improve upon the solubility and pharmacokinetic properties of this class of compounds while still maintaining potent antibacterial activity. We have found that the absolute stereochemistry at the 2-position of the pyrrolidine ring is critical to the maintenance of such activity. In this paper, we report the full details of the asymmetric synthesis and the in vitro and in vivo structure-activity relationships of this series of compounds as well as the physiochemical properties, such as water solubility and log P, associated with the structural modifications. We also discuss the pharmacokinetic properties of several of these compounds in mice and the pharmacokinetics of 59, which has the best overall properties of agents in this study, in dog.     

Involvement of ICAM-1 in bone metabolism: a potential target in the treatment of bone diseases?

Bone diseases such as osteoporosis, osteoarthritis and rheumatoid arthritis (RA) affect a great proportion of individuals, with debilitating consequences in terms of pain and progressive limitation of function. Existing treatment of these pathologies has been unable to alter the natural evolution of the disease and, as such, a clearer understanding of the pathophysiology is necessary in order to generate new treatment alternatives. One therapeutic strategy could involve the targeting of intercellular adhesion molecule-1 (ICAM-1; CD54). In bone, ICAM-1 is expressed at the surface of osteoblasts (Obs) and its counter-receptor, leukocyte function-associated antigen-1 (LFA-1; CD11a), at the surface of osteoclast (Oc) precursors. ICAM-1 blockade between the Ob and the pre-Oc results in an inhibition of Oc recruitment and a modulation of inflammation, which could potentially help in controlling disease activity in bone pathologies. So far, clinical studies on ICAM-1 blockade in bone diseases have been limited to RA. A better understanding of the implication of this adhesion molecule in Ob/Oc interactions and inflammatory mediation in the bone pathological state, however, is needed. As new discoveries on the role of this adhesion molecule are being reported, ICAM-1 could become a potential target for other bone diseases as well.     

Evaluation of the antinociceptive properties from Brillantaisia palisotii Lindau stems extracts

Brillantaisia palisotii Lindau is a plant belonging to Acanthaceae family and it is widely found in tropical regions. Some species of this family are used in the folk medicine to treat several disorders, mainly those that involve analgesic processes. In this work it was evaluated antinociceptive activities of dichloromethane, ethyl acetate and n-butanol extracts obtained from Brillantaisia palisotii stems in peripheral (acetic acid-induced writhing) and central (tail flick and hot plate) analgesic models. All three extracts significantly inhibited the total number of writhing in a dose dependent manner. A spinal antinociceptive effect was observed with all three extracts and with similar patterns to all doses (1-30 mg/kg). Although ethyl acetate extract did not demonstrate supra-spinal activity, the effects observed with dichloromethane extract showed analgesic effect with all doses. The n-butanolic extract had activity only with the lowest dose (1 mg/kg). Our results indicate that all extracts from Brillantaisia palisotti stems develop peripheral and spinal analgesic activity, being the dichloromethane extract the only one with supra-spinal analgesic effect.     

Evaluation of adolescent swimmers through a 30-s tethered test

Our purpose was to demonstrate that 30-s tethered swimming test can be a useful tool to estimate swimming performance in short distance freestyle events. Thirteen high level adolescent swimmers (7 male and 6 female of 16.6 ± 1.0 and 15.8 ± 0.8 years old) performed a 30-s maximum effort in front crawl tethered swimming. Afterward, subjects completed 50-m and 100-m freestyle events at the National Championships. Both maximum and mean force values obtained in the tethered test related directly with 50-m (r = .78 and r = .72, p < .01, respectively) and 100-m freestyle velocities (r = .63 and r = .61, p < .05, respectively). Fatigue index did not present a significant relationship with any of the studied performance variables. However, a proposed parameter--fatigue slope-correlated with 50-m (r = -.75, p < .01), 100-m performances (r = -.57, p < .05) and with r[La-] (r = -.90, p < .01). It is concluded that, for adolescent swimmers, values obtained from 30-s tethered test are well related with swimming performance in sprint events. In addition, fatigue slope seems to be more associated with swimming performance in short distance events than fatigue index.     

Isolated hypoglossal schwannoma in a 9-year-old child

The authors report a case of an isolated schwannoma of left hypoglossal nerve in a 9-year-old girl. To the authors' knowledge, this is the first case report of hypoglossal nerve schwannoma in the pediatric population in the absence of neurofibromatosis Type 2. The patient presented with a 2-month history of morning nausea and vomiting with occasional daytime headaches. Magnetic resonance imaging and subsequent CT scanning revealed a dumbbell tumor with a belly in the lower third of the posterior fossa and head underneath the left jugular foramen. Its neck protruded through an expanded hypoglossal canal. Although the lesion bore radiological characteristics of a hypoglossal schwannoma, the absence of hypoglossal palsy and the apparent lack of such tumors in the pediatric population the preoperative diagnosis was not certain. The tumor was approached via a midline suboccipital craniotomy, and gross-total resection was achieved. Pathological examination confirmed the diagnosis of schwannoma. Blood and tumor tests for mutations in the NF2 gene were negative. Postoperative mild hypoglossal palsy recovered by the 3-month follow-up, and an MRI study obtained at 1 year did not show recurrence.     

Induction of oxidative stress in brain of glutaryl-CoA dehydrogenase deficient mice by acute lysine administration

In the present work we evaluated a variety of indicators of oxidative stress in distinct brain regions (striatum, cerebral cortex and hippocampus), the liver, and heart of 30-day-old glutaryl-CoA dehydrogenase deficient (Gcdh(-/-)) mice. The parameters evaluated included thiobarbituric acid-reactive substances (TBA-RS), 2-7-dihydrodichlorofluorescein (DCFH) oxidation, sulfhydryl content, and reduced glutathione (GSH) concentrations. We also measured the activities of the antioxidant enzymes glutathione peroxidase (GPx), glutathione reductase (GR), catalase (CAT), superoxide dismutase (SOD) and glucose-6-phosphate dehydrogenase (G6PD). Under basal conditions glutaric (GA) and 3-OH-glutaric (3OHGA) acids were elevated in all tissues of the Gcdh(-/-) mice, but were essentially absent in WT animals. In contrast there were no differences between WT and Gcdh(-/-) mice in any of the indicators or oxidative stress under basal conditions. Following a single intra-peritoneal (IP) injection of lysine (Lys) there was a moderate increase of brain GA concentration in Gcdh(-/-) mice, but no change in WT. Lys injection had no effect on brain 3OHGA in either WT or Gcdh(-/-) mice. The levels of GA and 3OHGA were approximately 40% higher in striatum compared to cerebral cortex in Lys-treated mice. In the striatum, Lys administration provoked a marked increase of lipid peroxidation, DCFH oxidation, SOD and GR activities, as well as significant reductions of GSH levels and GPx activity, with no alteration of sulfhydryl content, CAT and G6PD activities. There was also evidence of increased lipid peroxidation and SOD activity in the cerebral cortex, along with a decrease of GSH levels, but to a lesser extent than in the striatum. In the hippocampus only mild increases of SOD activity and DCFH oxidation were observed. In contrast, Lys injection had no effect on any of the parameters of oxidative stress in the liver or heart of Gcdh(-/-) or WT animals. These results indicate that in Gcdh(-/-) mice cerebral tissue, particularly the striatum, is at greater risk for oxidative stress than peripheral tissues following Lys administration.