Withdrawal of repeated morphine enhances histamine-induced scratching responses in mice

An itch is experientially well known that the scratching response of conditions such as atopic dermatitis is enhanced under psychological stress. Morphine is typical narcotic drug that induces a scratching response upon local application as an adverse drug reaction. Although long-term treatment with morphine will cause tolerance and dependence, morphine withdrawal can cause psychologically and physiologically stressful changes in humans. In this study, we evaluated the effects of morphine withdrawal on histamine-induced scratching behavior in mice. Administration of morphine with progressively increasing doses (10–50?mg/kg, i.p.) was performed for 5 consecutive days. At 3, 24, 48, and 72?hr after spontaneous withdrawal from the final morphine dose, histamine was intradermally injected into the rostral part of the back and then the number of bouts of scratching in 60?min was recorded and summed. We found that at 24?hr after morphine withdrawal there was a significant increase in histamine-induced scratching behavior. The spinal c-Fos positive cells were also significantly increased. The relative adrenal weight increased and the relative thymus weight decreased, both significantly. Moreover, the plasma corticosterone levels changed in parallel with the number of scratching bouts. These results suggest that morphine withdrawal induces a stressed state and enhances in histamine-induced scratching behavior. Increased reaction against histamine in the cervical vertebrae will participate in this stress-induced itch enhancement.     

Impact of dosing regimen of custirsen,an antisense oligonucleotide,on safety,tolerability and cardiac repolarization in healthy subjects

Aims

Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide (ASO) that reduces clusterin production, is under investigation with chemotherapy in patients with solid tumours. Custirsen is associated with constitutional symptoms (CS) that may interfere with clinical pharmacology investigations, such as QT interval studies. Experience with other ASOs suggests NSAID premedication may ameliorate CS, but we observed suboptimal outcomes in healthy subjects given custirsen and NSAIDs. We sought to establish a custirsen regimen for future clinical pharmacology studies in healthy subjects.

Methods

Subjects received custirsen (640 mg intravenously over 120 min) with dexamethasone premedication or increasing doses (320, 480, 640 mg over 6 days) of custirsen with dexamethasone premedication, then one full custirsen dose without premedication on day 8. Incidence/severity of adverse events (AEs) and extensive electrocardiogram readings were evaluated. Pharmacokinetic parameters were estimated.

Results

AEs included CS, elevated transaminases and prolonged activated partial thromboplastin time (aPTT) that were predominantly grade 1/2. Administration of increasing custirsen doses and dexamethasone premedication reduced the incidence of CS associated with full dose custirsen. Transaminase elevation showed a dose-dependent effect (0% at days 2, 4, 27% at day 6) with the highest custirsen doses. Increasing doses of custirsen may have mitigated the severity but not incidence of aPTT prolongation. Neither regimen was associated with cardiac repolarization changes in QT values or concentration–effect analyses. The custirsen pharmacokinetic profile was consistent with previous experience.

Conclusion

Escalation of custirsen dose combined with dexamethasone premedication reduced CS associated with full dose custirsen and should be considered in future clinical pharmacology studies of custirsen.     

二甲基甲酰胺致心肌细胞损伤及维生素C保护作用的实验研究

目的 探讨二甲基甲酰胺(dimethylformamide,DMF)致H9c2心肌细胞损伤及维生素C(vitamin C,VC)对此损伤是否有保护作用.方法 观察DMF染毒及VC干预后心肌细胞及核形态改变;活性氧(reactive oxygen species,ROS)、总抗氧化能力(total antioxidant capacity,T-AOC)试剂盒检测不同浓度DMF染毒不同时间、特定浓度DMF合并不同浓度VC干预后细胞氧化应激水平变化.结果 DMF染毒后细胞及核形态出现不同程度异常,低浓度VC干预后有所改善;100、140、180、220、250 mM DMF染毒24h,100、140、180、200、220 mM DMF染毒48 h,100、125、140、180、200 mM DMF染毒72 h后,同时间不同剂量染毒,细胞ROS、T-AOC水平差异有统计学意义;同剂量不同时间染毒,细胞ROS、T-AOC水平差异有统计学意义(ROS:24 h:F=5 763.00,P＜0.001;48 h:F=5 861.00,P＜0.001;72 h:F =9 188.00,P＜0.001;T-AOC:24 h:F=6.25,P=0.004;48 h:F=11.48,P＜0.001;72 h:F=14.13,P＜0.001).VC (0.025、0.05、0.10、0.25 mM)干预后ROS、T-AOC水平与对照相比差异均有统计学意义(均有P＜0.05).结论 氧化损伤可能是DMF发挥毒性的重要机制;低剂量VC可缓解DMF产生的氧化损伤,对细胞产生保护效应.     

医务人员突发生物事件知识认知调查

目的：了解某三级综合性医院的医务人员对突发生物事件相关知识的认知现状。方法采用自行设计的调查问卷,对医院不同科室的医务人员进行调查。结果医务人员对各类突发生物事件知识掌握程度不一;不同专业、职务、学历、年龄组的医务人员突发生物事件知识得分差异具有统计学意义（P＜0．05）。结论医务人员突发生物事件相关知识掌握情况不理想,应采取多途径、全员、多层次提高医务人员对突发生物事件相关知识的认知水平。     

医务社工介入突发公共事件的探讨与反思

上海外滩踩踏事件当中,本院医务社工第一时间介入,在整个救治过程当中,为协助伤病员救治、安抚陪伴者情绪、为医务人员提供情绪支持等,发挥了应有的作用,为救治工作创造了平稳有序的环境,凸显了社工服务的重要性和有效性。本文将对医务社工全程参与救助过程的活动实务进行分析,探讨医务社工在突发公共事件当中的作用与意义。     

某院2013年1-6月药品不良反应报告分析

目的：：了解药品不良反应（ADR）发生特点,为促进合理用药,深入ADR检测提供依据。方法：对某医院2013年1~6月上报的50例ADR报告进行分类统计、分析。结果：50例ADR中,抗菌药物所占比例最高,共有10例（20.00%）。引发ADR的抗菌药物,依次为喹诺酮类（占60.00%）、头孢菌素类和青霉素类（占20.00%）。50例ADR累及多个器官或系统,最常见的是免疫系统（占34.00%）,其次为皮肤及附件损害（28.00%）和循环系统（26.00%）。结论：应控制抗菌药物的合理使用,加强ADR监测工作,促进合理用药。     

Reversible oligohydramnios in the second trimester of pregnancy in two patients with long-term diclofenac exposure

The use of non-steroidal anti-inflammatory drugs like diclofenac in the third trimester of pregnancy can cause severe side effects, in particular oligohydramnios, premature closure of ductus arteriosus, and fetal kidney damage. However, the treatment with non-steroidal anti-inflammatory drugs until gestational week 28 is accepted as relatively safe. Here we describe two retrospectively reported cases of early-onset oligohydramnios associated with long-term diclofenac exposure of at least 150 mg per day. The pathological findings were detected at gestational weeks 22 and 23, respectively. Amniotic fluid turned to normal after discontinuation of diclofenac in both cases, suggesting causality. Although early-onset oligohydramnios is a rare complication, caution for long-term diclofenac use in high doses is recommended even before gestational week 28.     

Applicability of the one-step DVS method for the determination of amorphous amounts for further different hydrophilic and hydrophobic drugs

In a former publication the authors showed that low amounts of amorphous content (LOQ of 0.5%) in a hydrophobic model API (Ciclesonide) can be measured with an individually adjusted one-step dynamic organic vapor sorption (DVS). In this investigation the applicability is tested on various APIs which differ in lipophilicity (poor water solubility) and hygroscopicity (absorption of water).The vapor sorption method proved to be applicable in almost all cases. Moisture sorption isotherms were determined for all five investigated crystalline and amorphous APIs. However, it was necessary to select the parameters individually for each API. The used solvents (water, methanol, isopropanol and methylene chloride) and the humidity-levels (0.05 p/p₀ until 0.5 p/p₀) were chosen carefully because otherwise the amorphous amounts switch to their crystalline counterparts and are not detectable. The production of fully amorphous samples (absence of crystalline material measured by DSC, mDSC and XRPD) was optimized over several trials. As successfully methods proved ball-milling, freeze-drying, spray-drying and/or quench cooling. In the next step these fully amorphous amounts were blended with crystalline starting material to calibration curves (Turbula blender, influence of electrostatic charge to homogeneity) for the calculation of amorphous content.In summary, the following presented methods were used to determine and quantify low amorphous amounts (between 1.5% and 17.0%) in jet-milled powders (grinding pressure of 8 bar, 1–3 grinding cycles), respectively.