Colonic delivery of dexamethasone from a prodrug accelerates healing of colitis in rats without adrenal suppression

Dexamethasone-β-d-glucuronide, a colon-specific prodrug of dexamethasone, may be useful in the treatment of ulcerative colitis and Crohn's colitis. The aim of this study was to evaluate colonic delivery and efficacy of this prodrug in the rat. Distribution of dexamethasone in luminal contents and tissues of the gastrointestinal tract and in plasma was measured after oral administration of dexamethasone-β-d-glucuronide or free dexamethasone. Efficacy of the prodrug and free drug was tested in an acetic acid-induced rat colitis model. Healing of induced colitis was assessed by measuring net intestinal fluid absorption, colonic surface area of ulceration, histology, and myeloperoxidase activity. Glucocorticosteroid toxicity was evaluated with serum corticosterone and plasma adrenocorticotropic hormone levels. The drug delivery index (a measure of relative targeting efficiency) was 6.7 and 8.6 in the cecal and colonic mucosa, respectively. The prodrug was significantly more potent than free drug in improving net colonic fluid absorption while significantly reducing surface area of ulceration and histological grade in colitic rats. Treatment with free dexamethasone significantly reduced serum corticosterone levels to subnormal levels, and treatment with the prodrug maintained serum corticosterone and plasma adrenocorticotropic hormone levels near control levels. The prodrug dexamethasone-β-d-glucuronide delivers efficacious amounts of dexamethasone to the large intestine from lower doses than free dexamethasone.     

Subunit-stoichiometric evidence for kir6.2 channel gating, ATP binding, and binding-gating coupling

ATP-sensitive K(+) channels are gated by intracellular ATP, allowing them to couple intermediary metabolism to cellular excitability, whereas the gating mechanism remains unclear. To understand subunit stoichiometry for the ATP-dependent channel gating, we constructed tandem-multimeric Kir6.2 channels by selective disruption of the binding or gating mechanism in certain subunits. Stepwise disruptions of channel gating caused graded losses in ATP sensitivity and increases in basal P(open), with no effect on maximum ATP inhibition. Prevention of ATP binding lowered the ATP sensitivity and maximum inhibition without affecting basal P(open). The ATP-dependent gating required a minimum of two functional subunits. Two adjacent subunits are more favorable for ATP binding than two diagonal ones. Subunits showed negative cooperativity in ATP binding and positive cooperativity in channel gating. Joint disruptions of the binding and gating mechanisms in the same or alternate subunits of a concatemer revealed that both intra- and intersubunit couplings contributed to channel gating, although the binding-gating coupling preferred the intrasubunit to intersubunit configuration within the C terminus. No such preference was found between the C and N termini. These phenomena are well-described with the operational model used widely for ligand-receptor interactions.     

血清总抗氧化水平测定用于重症患者临床监护的意义初探

目的 :采用化学比色全自动分析法测定血清 (或血浆 )总抗氧化水平 ,探讨血清总抗氧化物含量测定在临床监护重症患者过程中的意义。方法 :利用过氧化氢过氧化物酶系统与 2 ,2′ Azino di 3ethylbenzthiazoline sulphonate(ABTS)反应能被血清内总抗氧化物抑制的原理 ,根据显色反应受抑制大小与总抗氧化水平成正比关系来测定总抗氧化物含量 ,并对 36例重危患者在抢救治疗过程中的总抗氧化物含量进行测定。结果 :危重患者血清内总抗氧化物含量是非常低下的 ,当极其降低时预示着患者有死亡的危险。结论 :重危患者的血清总抗氧化物含量监测 ,对于了解病情严重程度及病情转归有一定价值     

浅析卫生政策类信息在传播中的误读——以“先诊疗后结算”为例

文章以媒体和受众对于卫生政策类信息“先诊疗后结算”的误读事件为例,并分析了其背后蕴含的原因,即网民不良情绪宣泄?政府与受众传播地位不对称和媒介“热岛效应”等,并结合实践探索性地提出了信息传播中政策类信息的传播方式?     

Acetic acid-induced colitis results in bystander ileal injury

The extent of the small intestinal injury following experimental acetic acid induction of colitis in rats was examined. Following intraluminal colonic administration of radiolabelled acetic acid, high levels of radioactivity were identified in the colon and in the liver, while low background levels were found in jejunum, ileum, caecum, and heart. The increased level of radioactivity in the liver relative to that of the heart suggests that a significant portion of the colonic intraluminal acetic acid was absorbed directly into the portal circulation. The colon, which was the only segment of intestine in direct contact with the acetic acid, had the highest levels of radiolabelled acetic acid, demonstrated a marked macroscopic mucosal ulceration, an enhanced myeloperoxidase activity, and a fall inin vivo fluid absorption. The jejunum, which demonstrated low levels of radiolabelled acetic acid was normal without evidence of injury. In contrast, the ileum, which displayed the same levels of radiolabelled acetic acid as did the jejunum, also demonstrated a significant fall inin vivo fluid absorption but showed no mucosal ulceration or increased myeloperoxidase activity.These studies have shown that acetic acid induction of colitis produces evidence of ileal injury but that this injury is not the result of inadvertent delivery of acetic acid or recruitment of neutrophils to the ileal mucosa.     

Rosiglitazone inhibits vascular KATP channels and coronary vasodilation produced by isoprenaline

BACKGROUND AND PURPOSE

Rosiglitazone is an anti-diabetic drug improving insulin sensitivity and glucose uptake in skeletal muscle and adipose tissues. However, several recent clinical trials suggest that rosiglitazone can increase the risk of cardiovascular ischaemia, although other studies failed to show such risks. Therefore, the effects of rosiglitazone on the coronary circulation and any potential vascular targets need to be elucidated. Here, we show that the vascular isoform of the ATP-sensitive K⁺ (K_ATP) channel is inhibited by rosiglitazone, impairing physiological regulation of the coronary circulation.

EXPERIMENTAL APPROACH

The K_IR6.1/SUR2B channel was expressed in HEK293 cells and studied in whole-cell and inside-out patch configurations. The Langendorff heart preparation was used to evaluate rosiglitazone in the coronary circulation of wild-type (WT) and K_IR6.1-null (Kcnj8^−/−) mice.

KEY RESULTS

K_IR6.1/SUR2B channels in HEK cells were inhibited by rosiglitazone in a membrane-delimited manner. This effect was markedly enhanced by sub-micromolar concentrations of glibenclamide and the IC₅₀ for rosiglitazone fell to 2µM, a therapeutically achievable concentration. In the Langendorff heart preparation rosiglitazone inhibited, concentration-dependently, the coronary vasodilation induced by isoprenaline, without affecting basal coronary tone. Effects of rosiglitazone on coronary perfusion were attenuated by more than 50% in the Kcnj8^−/− mice, supporting the involvement of K_ATP channels in this effect of rosiglitazone on the coronary circulation.

CONCLUSIONS AND IMPLICATIONS

These results indicate that the vascular K_ATP channel is one of the targets of rosiglitazone action, through which this drug may compromise coronary responses to circulating vasodilators and perhaps also to metabolic stress.     

化学发光法测定超氧化物歧化酶

采用海萤萤光素诱导剂作为化学发光剂，以黄嘌呤－黄嘌呤氧化酶体产生超氧阴离子，用ＫＣＮ络合铜锌离子，使铜锌超氧化物歧化酶失活，建立了检测血浆及红细胞ＳＯＤ酶活性的ＣＬＡ化学发光法。     

Effects of early-life exposure to THIP on phenotype development in a mouse model of Rett syndrome

Background

Rett syndrome (RTT) is a neurodevelopmental disorder caused mostly by disruptions in the MECP2 gene. MECP2-null mice show imbalances in neuronal excitability and synaptic communications. Several previous studies indicate that augmenting synaptic GABA receptors (GABA_ARs) can alleviate RTT-like symptoms in mice. In addition to the synaptic GABA_ARs, there is a group of GABA_ARs found outside the synaptic cleft with the capability to produce sustained inhibition, which may be potential therapeutic targets for the control of neuronal excitability in RTT.

Methods

Wild-type and MECP2-null mice were randomly divided into four groups, receiving the extrasynaptic GABA_AR agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride (THIP) and vehicle control, respectively. Low-dose THIP was administered to neonatal mice through lactation. RTT-like symptoms including lifespan, breathing, motor function, and social behaviors were studied when mice became mature. Changes in neuronal excitability and norepinephrine biosynthesis enzyme expression were studied in electrophysiology and molecular biology.

Results

With no evident sedation and other adverse side effects, early-life exposure to THIP extended the lifespan, alleviated breathing abnormalities, enhanced motor function, and improved social behaviors of MECP2-null mice. Such beneficial effects were associated with stabilization of locus coeruleus neuronal excitability and improvement of norepinephrine biosynthesis enzyme expression.

Conclusions

THIP treatment in early lives might be a therapeutic approach to RTT-like symptoms in MECP2-null mice and perhaps in people with RTT as well.

     

颗粒增强免疫透射比浊测定血中Cyst C全自动分析法的建立与评价

目的：建立颗粒增强免疫透射比浊测定血中胱蛋白酶抑制剂C（Cyst C）全自动分析,评价该法常规用于检测血中胱蛋白酶抑制剂C的可行性。方法：将含有Cyst C血样本与乳胶颗粒增强的Cyst C多克隆兔抗体按一定体积比混合,在一定量的兔免疫球蛋白及表面活性剂存在条件下,抗原、抗体结合反应在一定温度、时间内产生一定大小的颗粒,许多颗粒在反应液体中形成一定的浊度,利用Olympus AU2700全自动生化分析仪透射比浊测定,并对方法的不精密度、准确度、干扰试验及与Dade Behring BN ProSpeC免疫散射比浊测定方法比较等进行评价。结果：Cyst C浓度为1．03mg／L、5．67mg／L样本的批内不精密度CV分别为4．8％、1．9％。向Cyst C浓度为0．79mg／L、1．18mg／L、1．46mg／L、2．46mg／L样本中加入1．65mg／L的标准液测定回收率分别为100％、95％、85％、87％,平均回收率为92％。样本中的类风湿因子、胆红素、血红蛋白、三酰甘油等干扰物浓度分别达975U／ml、400μmol／L、5g／L、6．7mmol／L时对检测无显著性影响。Cyst C浓度在0．41mg／L～6．60mg／L范围内检测线性良好。血清、肝素抗凝血浆及EDTA抗凝血浆样本测得的Cyst C结果未发现显著性差异（F=0．065,P=0．938）。与Dade Behring BN ProSpeC免疫散射比浊测定方法比较有良好的相关性,Y=0．98x-0．054,r=0．997,P〈0．01,但两者存在非常显著性差异（P〈0．01）,本法结果较Dade Behring BN ProSpeC免疫散射仪测定结果略低,两种方法的平均偏差为-0．0678mg／L。结论：建立的颗粒增强免疫透射比浊法测定血Cyst C重复性好、准确度高。血清、肝素抗凝血浆及EDTA抗凝血浆均可用于分析。测定不受类风湿因子（≥975U／ml）,胆红素（≥400μmol／L）,血红蛋白（≥5g／L）及三酰甘油（≥6．7mmol／L）的干扰。与Dade Behring BN ProSpec免疫散射比浊测定方法测定结果比较有良好的相关性,适用于在全自动生化分析仪上作常规检测。