Amiodarone Toxicity: II. Desethylamiodarone-Induced Phospholipidosis and Ultrastructural Changes during Repeated Administration in Rats

The contribution of desethylamiodarone (DEA), principal metaboliteof the antiarrhythmic drug amiodarone, to the major side effectsof amiodarone is unclear. The effects of repeated DEA administrationto rats on tissue drug accumulation, ultrastructural changes,and phospholipid concentrations were studied. Two groups (n= 8/group) of male Sprague-Dawley rats (250 g body wt) wereadministered a 5% aqueous solution of DEA (Dose I, 40 mg/kg/day,Dose II, 60 mg/kg/day) intraperitoneally for 21–23 days,while a third group (control, n = 8) received saline. DEA levelswere significantly higher with Dose II compared to Dose I inthe lung, liver, kidney, spleen, heart, and serum while thetissue to serum ratios were similar with both doses for alltissues except the heart. DEA administration caused a significantelevation in the lipid phosphorus levels of liver, lung, andalveolar macrophages compared to control levels. A strong positivecorrelation (p < 0.01) was found between tissue DEA levelsand lipid phosphorus for the above tissues. Electron microscopyrevealed the presence of lipid inclusion bodies in liver, lung,and alveolar macrophages of DEA-treated rats. A dose-dependentincrease in the percentage of vacuolar surface area was foundin the lung and alveolar macrophages. The tissue ultrastructuralchanges after repeated DEA dosing were qualitatively similarto our previous findings with amiodarone. Increased lung andliver phospholipid levels with repeated DEA doses may resultfrom a potent inhibitory action of DEA on tissue phospholipaseA as has been observed by others in in vitro studies.     

Elimination and Accumulation of the Rodenticide Flocoumafen in Rats Following Repeated Oral Administration

1. Following multiple oral administration of ¹⁴C-flocoumafen to rats at 0·02 and 0·1 mg/kg per week, appreciable cellular accumulation was seen in the liver.

2. Residues in the liver increased with dose throughout the duration of the experiment (14 weeks) at the low dose, but reached a plateau after 4 weeks at the high dose. The major component was unchanged flocoumafen together with a minor polar metabolite seen also in faeces.

3. The data suggest the presence in rat liver of a saturable high-affinity binding site for flocoumafen and a second binding site of lower affinity.

4. Lethal anticoagulant action occurs only when the binding sites have become saturated.

5. A range of haematological and clinical chemistry measurements failed to predict the onset of anticoagulant tocicity seen in the high dose treatment group.

6. Flocoumafen was not extensively metabolised; at the low dose, approximately 30% of the cumulative administered dose was eliminated in the faeces within 3 days of each dosing, mainly as unchanged rodenticide. At the high dose, this value ranged from 18% after the first dose to 59% after the tenth dose.

7. Two more polar metabolites and a lipophilic compound were minor products in faeces. Amounts of the polar products increased with cumulative dosage received. The urinary route of elimination was a very minor one (< 1·6%) at both doses.     

奥硝唑对大鼠睾丸和附睾超微结构的影响

目的 考察奥硝唑(ORN)对雄性大鼠睾丸、附睾超微结构的影响.方法 选取健康成年雄鼠40只,随机分成正常组(1%CMC-Na溶液)、ORN低、中、高剂量组(100、400和800 mg·kg-1·d-1),连续灌胃给药20 d.于末次给药24 h后取材,常规电镜制片,透射电镜观察各组睾丸、附睾超微结构.结果 电镜观察显示:(1)低剂量组睾丸、附睾超微结构与正常对照组无明显差异;(2)中剂量组附睾主细胞内可见空泡;睾丸少数生精小管层次紊乱,线立体肿胀、嵴模糊,胞质中其它细胞器偶见肿胀、溶解、空泡化现象;(3)高剂量组附睾管壁主细胞含空泡,纤毛排列紊乱,附睾管腔可见大量异型精子及坏死细胞残留物.睾丸牛精小管细胞胞质含有大量空泡;变态完成的精子数目很少;生精管腔填满了坏死脱落的各种细胞;部分精子顶体膜破裂,尾部轴丝包膜水肿起皱.结论 奥硝唑中、高剂量能引起附睾、睾丸发生超微病理改变.病理改变的部位和程度与剂量相关.     

Drug Induced Changes in 3H-Catecholamine Accumulation after 3H-Tyrosine

The accumulation of ³H-DA and ³H-NA in the caudate nucleus, remainder of the brain, spinal cord and heart was measured 15 minutes after ³H-tyrosine administered intravenously into rats pretreated with drugs. Apomor-phine as well as stimulating DA receptors reduced ³H-DA when given shortly before ³H-tyrosine, probably due to a negative feed-back. When given 30 minutes or 3 hours previously, ³H-NA was increased, probably indicating the importance of DA neurone activity for NA activity. Clonidine which stimulates NA receptors, did not significantly reduce ³H-NA as expected by feed-back. Pimozide, which blocks DA but apparently not NA receptors, not only increased ³H-DA but also ³H-NA. Haloperidol and chlorpromazine which block DA and NA receptors, only increased ³H-DA. Thioridazine, however, also increased ³H-NA. The complicated balance between the tendency for an increase of NA turnover by the direct feed-back mechanism, and the counteracting inhibition from a reduced stimulation from the DA neurones, seems to be a contributary factor. LSD which stimulates the 5-HT receptors increased the ³H-catecholamines both centrally and peripherally. The effect of d-amphetamine was studied in some experiments, the most striking effect being an increase in ³H-DA after an intravenous injection of the drug. Lithium carbonate increased ³H-NA and probably also ³H-DA. Phenoxybenzamine, which blocks NA receptors, increased ³H-NA via feed-back regulation.     

羟基喜树碱缓释片在大鼠脑内的释放情况研究

目的:考察羟基喜树碱(HCPT)缓释片植入大鼠脑内的释放情况。方法:将HCPT缓释片植入40只SD大鼠脑内,分别于第1、3、7、10、13、17、21、28天时处死大鼠,取出残留缓释片采用高效液相色谱法考察其未释放的药量并计算累积释放百分率;另取大鼠血浆和脑组织检测其中药物浓度。结果:HCPT缓释片在大鼠脑内第1、28天的累积释放百分率分别为(12.13±7.58)%、(72.31±15.17)%,表明其释放时间达28d以上;其在大鼠脑组织和血浆中第28天的药物浓度分别为(135.41±17.48)μg·mL-1、(133.75±10.81)ng·mL-1,表明在脑组织中的药物浓度明显高于在血浆中的浓度。结论:自制的HCPT缓释片在大鼠脑内有较好的缓释效果,且可降低全身性毒副作用。     

多西他赛自微乳注射液在大鼠体内药动学及组织分布

目的测定大鼠单剂量（12．55mg／kg）尾静脉注射多西他赛自微乳溶液和市售注射剂的血药浓度,比较2组的药动学行为;研究多西他赛自微乳溶液和市售注射剂在正常大鼠心,肝,脾,肺,肾中的分布情况。方法采用高效液相法测定sD大鼠给药后不同时问点的血药浓度以及组织分布情况。结果多西他赛自微乳溶液组和市售制剂组的主要药动学参数除表观分布容积VI／F外,t1/2β,CL、AUC0→∞、MRT0→∞均无显著性差异（P〉0．05）。结论自制微乳与市售制剂在大鼠体内具有相似的动力学特征,没有显著改善药物在大鼠体内的组织分布。     

Bisphenol A Exposure Impairs Epididymal Development during the Peripubertal Period of Rats: Inflammatory Profile and Tissue Changes

Bisphenol A (BPA) is a synthetic non‐steroidal oestrogen used in the production of plastics. BPA can cause alterations in the endocrine system of human beings and animals at varied stages of development. During puberty, altered morphological, sexual behaviour and completion of the epididymal development occur. Therefore, this study aimed to evaluate the effects of BPA on epididymal development during the peripubertal period of rats. Male Wistar rats were treated with BPA via gavage at doses of 20 μg/kg or 200 μg/kg per day [post‐natal day (PND] 36–66). The control group received the vehicles under the same conditions. Feed and water were provided ad libitum. On PND 67, the epididymis was removed, weighed, divided into caput/corpus and cauda sections. It was then used for sperm count determination; histopathological and stereological evaluation; inflammatory cell enzymatic profiling (myeloperoxidase activity – MPO; N‐acetylglucosaminidase – NAG); immunohistochemistry for IL‐6; and evaluation of superoxide anion levels and malondialdehyde (MDA). Exposure to BPA at 200 μg/kg caused a significant increase of MPO activity and immunoreactivity to IL‐6 (interleukin‐6) as well as remodelling of tissue components in the caput/corpus and cauda regions of the epididymis. Under these experimental conditions, it is concluded that BPA alters post‐natal epididymal development.     

山东药监系统"抓基础、抓基层、抓作风和加强药品市场监管"的调查与思考

为深入了解山东省各地抓基础、抓基层、抓作风和加强药品监管的情况,研究制定下一步的工作重点,最近我们深入到全省17个市及其50多个县(市、区)进行调研,对今后一个时期全省药监系统如何更深入地做好"三抓一加强"进行了认真思考.     

RANKL OPG在去卵巢大鼠骨组织中蛋白表达动态变化

目的研究去卵巢后大鼠骨组织中RANKL、OPG蛋白表达的动态变化规律。方法建立去卵巢大鼠模型,于术后2、4、6、8、10周取股骨髁,DXA测量股骨髁的骨密度,HE染色观察骨质疏松情况,免疫组化检测骨组织RANKL、OPG蛋白表达情况。结果大鼠去卵巢6周后股骨髁骨密度开始降低,与对照组相比差异均具有显著性(P<0.05);HE染色显示去卵巢后骨小梁逐步变细,稀疏;组化显示骨髓内细胞RANKL染色强度随着去卵巢时间的延长而明显增强,OPG染色强度2周时较强,以后OPG染色强度逐渐降低。结论RANKL持续高表达,OPG表达短期内升高,迅速降低是绝经后骨质疏松的直接原因。     

Hyperresponsive Airways Correlate with Lung Tissue Inflammatory Cell Changes in Ozone-Exposed Rats

The role of inflammatory cell infiltration in the development of hyperresponsiveness of the airways to muscarinic challenge remains poorly understood. Unlike previous investigations that only examined conducting airway inflammation, the present study utilized both bronchoalveolar lavage (BAL) and lung tissue digestion to determine rat lung inflammatory cell contents following a 4-h exposure to 2 ppm ozone. Immediately following ozone exposure, neutrophil content of the lung tissue was significantly increased and reached a value that was fourfold higher than air-exposed controls by 3 h postexposure. Although lavage-recovered neutrophils were elevated at 24 h, tissue neutrophil numbers had returned to control values. This transient elevation of tissue neutrophils directly correlated with an elevation and subsequent decline of airway hyperresponsiveness, measured as a decrease in the intravenous dose of methacholine provoking a 200% increase in airway resistance (PD 200 R). Animals rendered neutropenic with a rabbit anti-rat neutrophil serum prior to exposure were protected from ozone-induced hyperresponsive airways, further demonstrating an association between neutrophil infiltration into the lung and altered airway physiology. Although BAL-recovered neutrophils demonstrated no adverse effects as a result of ozone exposure, macrophages were not only found to be necrotic but also displayed altered oxidative metabolism when challenged with phorbol myristate acetate. Thus, changes in the microenvironment of the airways smooth muscle were shown to be associated with transient accumulation of neutrophils within the lung tissue and abnormalities of bronchoalveolar lavage-recovered macrophages.     

Effect of Aluminium Hydroxide Administration on Normal Mice: Tissue Distribution and Ultrastructural Localization of Aluminium in Liver

Abstract: In order to assess the risk of parenteral aluminium (Al) exposure, we evaluated the effects of intraperitoneal administration of aluminium hydroxide, a compound widely used in medicine. Mice (strain Pzh:SFIS) received intraperitoneally, every two weeks 1 mg Al or 0.1 mg Al for five days a week. Controls received injections of saline. Al concentrations in liver, bone and brain were evaluated by electrothermal atomic absorption spectrometry after exposure to 2 mg, 4 mg, and 6 mg Al. The concentration was the highest in liver and occurred after exposure to only 2 mg Al (265.1±27.7 mg/kg, 233.5±28.0 mg/kg). Generally further accumulation was not dose- and treatment-dependent. The only exception was a significant Al increase in the liver after exposure to 6 mg Al. injected 0.1 mg Al five days/week. Development of resorption granulomas was observed in the liver, Al being revealed by Morin fluorescence in constituent macrophages and giant cells. By electron probe X-ray microanalysis, Al was identified predominantly in lysosomes of macrophages and Kupffer cells. In tibia of mice, a dose-dependent Al accumulation was observed. The highest level of Al concentration after the 6 mg treatment was 23.5±3.82 mg/kg and 25.06±2.3 mg/kg. The Al concentration in the brain of mice had not changed significantly during Al treatment.     

实施行政执法责任制加强药品监督机构建设

实施行政执法责任制 ,是对承担行政执法职能的机构提出的一种管理要求 ,对于落实依法治国 ,加强社会主义法制建设具有重要意义。山东省药品监督管理局下发了《行政执法过错责任追究办法》 ,使药品监督管理走向法治化。“有法可依 ,有法必依 ,执法必严 ,违法必究”的原则 ,在药品监督工作中得到了贯彻与实施。通过落实执法责任 ,规范了执法行为 ,提高了执法水平和执法效率 ,真正做到了依法行政。1　实施执法责任制的要求1 1　理顺关系 ,明确执法机构的职责实施执法责任制 ,首先要明确监督机构的职责。对此 ,《药品管理法》及《药品管理法实…     

2018年美国食品药品监督管理局批准的新药

<正>2018年美国食品药品监督管理局(Food and Drug Administration, FDA)共批准了43个新分子实体(new molecular entity,NMEs)和23个新生物制剂(biologic license applications,BLAs),该数字较2017年的56个,增加了10个(17. 9%)。按照药物作用分类,抗肿瘤药物18个(27. 3%),心血管系统药物12个(18. 2%),呼吸系统药物2个(3.0%),神经系统用药8个(12. 1%),内分泌用药9个(13.6%),抗感染药9个(13.6%),其他药物7个(10. 6%)。     

胺碘酮在临床用药中的药物相互作用研究

目的：通过对真实世界的胺碘酮药物相互作用的分析与评价,为临床合理用药提供参考。 方法：收集2018年1月1日至2019年12月31日某院门急诊患者的胺碘酮处方,剔除用药总数＜2种的处方,采用Lexicomp^® 、Stockley''s Drug Interactions以及药品说明书对其进行分析,评价药物相互作用的严重程度。结果：共收集到2987张胺碘酮相关的处方,筛选出与胺碘酮相关的DDIs的处方共2532张, 占84.77%,与胺碘酮有关的DDIs数为4809种,其中X级94种,D级742种,C级3973种,以C级占比最多,为82.62%;美托洛尔、华法林和氟哌噻吨分别是引起胺碘酮C级、D级、X级DDIs最为常见的药物 (12.31%、12.27%、1.66%),其不良结果主要有：①增加低血压风险,②增加华法林的血药浓度和抗凝作用,③增加QT间期延长风险。Logistic回归分析显示,合并用药种数与胺碘酮有关的DDIs的发生具有独立相关性(P＜0.001)。合并用药种数≥5种与胺碘酮有关的DDIs的发生风险较合并用药种数2-4种高(OR 10.884,95% CI 6.821-17.365)。结论：胺碘酮与多种常用药物存在相互作用,多药合用是致胺碘酮DDIs的危险因素。重视与胺碘酮有关的DDIs风险,在处方前置审核系统中完善其DDIs的监测和预警,以避免潜在药源性损害的产生,提高医疗质量。     

Synthesis and Solubility of Collagen in Rats during Recovery after High-dose Cyclophosphamide Administration

Abstract: The metabolism of collagen and mineral was studied during a nine-day postmedicational period in young, male rats receiving high-dose intraperitoneal cyclophosphamide treatment every second day for 12 days. Two days after ending medication the white blood cell counts (WBC) were reduced by about 70%. Both synthesis and solubility of collagen were suppressed by the present medication 2 days after termination of treatment. This suppression continued throughout the 9-day postmedicational period in bones, whereas in connective tissue of porous, ceramic implants both total collagen and the amount of salt soluble collagen regained normal values 9 days after cessation of treatment. Increased mineralization was found 2 days after ending medication and this high degree of mineralization persisted during the postmedicational period studied. Serum albumin levels were reduced and no increases were detected during the postmedicational period. The suggestion is made that the general protein synthesis is affected by high-dose cyclophosphamide administration.     

药品价格及其管理政策的英国经验启示

目的为我国政府制订药品价格及其管理政策提供参考。方法阐述英国药品价格及其管理政策,并对其效果进行分析和评价,最后针对我国国情提出建议。结果与结论我国应按照经济规律对市场进行监管;充分发挥非政府组织机构的作用,支持和服务于国家的药品监督和管理;对药品价格实行分类管理;使药品价格政策制订过程科学化;建立政府定价及市场价格监督机制;尽快建立药品价格管理的法律体系。     

浅议药品监督管理中的裁量行政行为

文章在对行政法中相关理论进行阐述的基础上,结合药品监督管理实践进行论证分析,认为把握适当原则、采取一定措施,对药品监督管理中的裁量行为进行规范,有益于裁量行政行为的合理实施.     

试论药品监督管理的全面质量管理意识

针对我国药品监督管理现状，阐述了加强现代质量管理意识的必要性和迫切性，着重强调了人员素质和标准化工作在全面质量管理中的重要作用。     

Tissue Distribution of [14C]Sucrose Octasulfate following Oral Administration to Rats

Purpose. Aluminum sucrose octasulfate (SOS) is used clinically to prevent ulcers. Under physiologic conditions, the sodium salt of this drug can be formed. Our objective was to determine whether sodium SOS was absorbed when administered orally. In addition to furthering our understanding of aluminum SOS, this study also aimed to clarify how other polyanionic drugs, such as heparin and low-molecular-weight heparins, are absorbed. Methods. [¹⁴C]-labeled and cold sodium SOS (60 mg/kg) were given to rats by stomach tube. Radioactivity was counted in gut tissue, gut washes, and nongut tissue (i.e., lung, liver, kidney, spleen, endothelial, and plasma samples) at 3 min, 6 min, 15 min, 30 min, 60 min, 4 h, and 24 h, and in urine and feces accumulated over 4 h and 24 h. Results. Peak radioactivity was found in the tissue and washes of the stomach, ileum, and colon at 6 min, 60 min, and 4 h, respectively, showing progression through the gut. Gut recovery accounted for 84% of the dose at 6 min but only 12% of the dose at 24 h, including counts from feces. Radioactivity was recovered from nongut tissue (averaging 8.6% of the dose) and accumulated urine (18% of the dose at 24 h). When total body distribution was considered, the recovery of radioactivity was greater for the endothelium than for plasma (peak percentage of the dose was 65% at 15 min, 20% at 3 min, 5% from 20 to 240 min for the vena cava, aortic endothelium, and plasma, respectively). Conclusions. Results indicate that sodium SOS is absorbed, agreeing with previous studies demonstrating the oral absorption of other sulfated polyanions. Endothelial concentrations must be considered when assessing the pharmacokinetics of these compounds. The measured plasma drug concentrations reflect the much greater amounts of drug residing with the endothelium.     

大鼠口服雄黄后唾液、血液及组织中砷浓度相关性研究

目的：建立唾液中砷浓度的测定方法,明确体内砷在唾液与血液及组织浓度之间的相关性。方法：大鼠分高、低剂量组（7．0g·kg-1和3．5g·kg-1）单次口服雄黄后采集血液、唾液和各组织样品,原子荧光光谱法测定血液及组织中砷的含量,石墨炉原子吸收光谱法测定唾液中砷的含量,线性回归法计算唾液中砷浓度与血液及各组织间的相关关系。结果：砷在大鼠唾液中有一定分布,且颌下腺中砷浓度高于腮腺。腮腺唾液中砷浓度与血液及心脏、肝脏和肺脏之间具有良好相关关系。结论：通过测定唾液中砷浓度,可以了解血液及组织中砷的分布情况,为重金属中毒的预防、诊断和治疗提供了新的思路扣切实可行的测定方法。