Neuroexcitatory actions of Tamiflu and its carboxylate metabolite

Oseltamivir (Tamiflu) is now being stockpiled by several governments as a first line treatment for an anticipated outbreak of avian influenza caused by H5N1. However, abnormal behaviors and death associated with the use of Tamiflu have developed into a major issue in Japan where Tamiflu is often prescribed for seasonal influenza. Thus, it is critical to determine neuropsychiatric effects of oseltamivir and to establish methods for safe administration. Using juvenile rats and rat hippocampal slices, we investigated whether oseltamivir has adverse effects on the central nervous system. Systemic injection of oseltamivir (50 mg/kg i.p.) produced no change in behavior within 2 h. However, prior injection of oseltamivir significantly altered the duration of loss of lightning reflex following ethanol injection (3.3 g/kg, i.p.). Ethanol injection in the presence of oseltamivir also resulted in enhanced hypothermia. In the CA1 region of hippocampal slices, oseltamivir (100 μM) induced paired-pulse facilitation in population spikes without changes in excitatory postsynaptic potentials. Similarly, 3 μM oseltamivir carboxylate, the active metabolite of oseltamivir, facilitated neuronal firing, though the facilitation did not involve GABAergic disinhibition. Moreover, oseltamivir carboxylate produced further facilitation following administration of 60 mM ethanol. These findings indicate that oseltamivir has effects on the central nervous system, especially when combined with other agents.     

A retrospective observational study of the treatment of a nosocomial infection caused by oseltamivir-resistant influenza virus A with baloxavir marboxil

BackgroundNosocomial (hospital-acquired) influenza A virus infection is a very important clinical issue. The objective of this study is to describe the effect of baloxavir marboxil in controlling an outbreak of this infection.MethodsA retrospective observational study was performed to assess the effectiveness of baloxavir marboxil in the treatment of nosocomial infections caused by oseltamivir-resistant influenza virus A.ResultsIn September 2019, there was an outbreak of nosocomial influenza A(H1N1)pdm09 viral infection in one out of three facility wards for inpatients at the Okinawa Nanbu Regional Center for Children with Special Needs. Symptomatic staff members were kept off duty until they remained afebrile for 2 days. Prophylactic oseltamivir was administered to inpatients (n = 37) and to staff members (n = 16) who voluntarily requested the drug. However, both inpatients and staff members showed influenza A infection during prophylactic use of oseltamivir. The A(H1N1)pdm09 virus sample obtained from one patient was shown to be oseltamivir-resistant. After administration of baloxavir marboxil, the nosocomial outbreak gradually ceased. Moreover, the time (hours) to alleviation of fever in the oseltamivir group (n = 11) and baloxavir marboxil group (n = 13) was significantly different (p = 0.0034).ConclusionOur report provides evidence for the usefulness of baloxavir marboxil in treating influenza A patients who have received prophylactic doses of oseltamivir. This is the first report describing the successful use of baloxavir marboxil for of a nosocomial outbreak caused by oseltamivir-resistant influenza A virus.     

小儿肺热咳喘口服液联合奥司他韦治疗小儿病毒性肺炎的临床研究

目的探讨小儿肺热咳喘口服液联合磷酸奥司他韦颗粒治疗小儿病毒性肺炎的临床疗效。方法选取2017年3月—2018年2月中国人民解放军第306医院收治的病毒性肺炎患儿124例为研究对象,按照随机数字表法分为对照组和治疗组,每组各62例。对照组口服磷酸奥司他韦颗粒,体质量15 kg 30 mg/次,15～23 kg 45 mg/次,23～40 kg 60 mg/次,40 kg 75 mg/次,2次/d。治疗组在对照组治疗的基础上口服小儿肺热咳喘口服液,1～3岁,10m L/次,3次/d;4～7岁,10m L/次,4次/d;8～12岁,20 mL/次,3次/d。两组患儿均连续治疗5 d。观察两组的临床疗效,比较两组的临床改善情况和细胞因子水平。结果治疗后,对照组和治疗组的总有效率分别为80.65%、93.55%,两组比较差异有统计学意义(P0.05)。治疗后,治疗组体温恢复正常时间、咳嗽消失时间、肺啰音消失时间短于对照组,两组比较差异有统计学意义(P0.05)。治疗后,两组C反应蛋白(CRP)、白细胞介素-6(IL-6)、基质金属蛋白酶9(MMP-9)、肿瘤坏死因子α(TNF-α)水平均显著降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗组细胞因子水平明显低于对照组,两组比较差异具有统计学意义(P0.05)结论小儿肺热咳喘口服液联合磷酸奥司他韦颗粒治疗小儿病毒性肺炎具有较好的临床疗效,能改善临床症状,调节细胞因子水平,具有一定的临床推广应用价值。     

Recent changes in the trends of seasonal influenza outbreaks in the Nagano Prefectural area of Japan: an oseltamivir effect?

We carried out a study to assess the pharmacological role of oseltamivir in the regulation of influenza epidemics in Japan, examining data for the years 1998 to 2006 from Nagano Prefecture. Oseltamivir is effective for the treatment of influenza, and its use in Japan has increased in the 3 years from 2003 to 2006. We found that, in the Nagano Prefectural area, the peak in the number of influenza infections showed a deviation to later periods after the 2003 season. and after 2003, it also took a longer time to reach the end of the seasonal epidemics of influenza infections compared with data from 1998 to 2002. To prevent influenza outbreaks having a long duration, we believe that the period of isolation in patients receiving anti-influenza drugs has to be reconsidered.     

重症甲型H1N1流感34例临床分析

目的分析重症甲型H1N1流感患者的临床特征,总结和探讨其治疗方法。方法回顾性分析2009年10月至12月入住ICU的34例危重症甲型H1N1流感患者的临床资料。结果患者年龄3个月～60岁,平均(13.9±4.5)岁,7岁患者24例。发热、咳嗽、进行性呼吸困难为主要症状。WBC总数正常范围21例(61.8%),下降7例(20.6%),增高6例(17.7%)。淋巴细胞正常16例(47.1%),下降6例(17.7%),增高12例(35.3%)。胸片示双肺野或单侧肺小斑片状模糊阴影。肺部CT示弥漫性间质性病变、胸腔积液或支气管扩张。肝功能酶谱和心肌酶谱指标均异常。30例应用奥司他韦、利巴韦林抗病毒治疗,4例使用激素,6例使用丙种球蛋白治疗。8例行气管插管机械通气,5例行无创机械通气治疗。34例患者全部好转或痊愈出院。结论肺、心、肝是甲型H1N1流感病毒损伤机体的主要脏器。机械通气支持治疗是抢救危重症患者的重要手段。     

甲型H1N1流感二例报告并文献复习

目的提高对甲型H1N1流感的认识以及探讨中西医结合治疗的疗效。方法结合2例甲型H1N1流感患者的临床资料进行文献复习,并对甲型H1N1流感并发白细胞变化、肝肾功能异常进行分析。结果2例患者入院前均有发热症状,体温38.0℃以上,2次鼻咽拭子甲型H1N1流感病毒逆转录-聚合酶链反应（RT-PCR）核酸检测均为阳性,诊断为甲型H1N1流感。入院后给予盐酸奥司他韦抗病毒治疗,以及中药和对症治疗。体温正常第4天,完成5d的抗病毒疗程后第1天和第2天开始出现甲型H1N1流感病毒核酸检测阴性。治疗过程中均有白细胞异常、淋巴细胞的变化和肾功能异常。甲型H1N1流感病毒核酸检测阳性持续5-7d从发病到恢复。结论甲型H1N1流感并发症较轻,中西医结合治疗效果明显。     

Oseltamivir decorated gold nanorods for visible rapid detection of influenza virus

In the present study, we developed a novel colorimetric strategy for the visible rapid detection of the influenza virus based on the unique optical properties of gold nanorods. Specifically, lipoic acid-modified Oseltamivir (OS), which is a strong neuraminidase inhibitor and used as the first-line drug in the treatment of influenza, was synthesized and further attached to the surface of gold nanorods (OS-LA-GNRs). The absorption band and density of OS-LA-GNRs were changed with the decreasing distance between the nanoparticles induced by the target-specific aggregation via strong neuraminidase–OS binding. All of these could be visible with the naked eyes and measured by UV-visible spectrophotometry. The results showed that our system had a comparable limit of detection (LOD) to the commercial colloidal gold stripes, making it feasible for wide diagnostic applications.     

帕拉米韦对比奥司他韦治疗儿童流感的系统评价和药物经济性分析

目的：系统评价帕拉米韦对比奥司他韦治疗儿童流感有效性和安全性,为临床治疗提供循证参考。方法：计算机检索中英文数据库,检索帕拉米韦对比奥司他韦治疗儿童流感的随机对照研究（RCT）,筛选文献、提取资料,并评价纳入研究的偏倚风险后,采用RevMan5.3软件进行Meta分析,并采用Tree Age Pro 2011软件运用决策树模型进行药物成本-效用分析。结果：共纳入17个RCT,合计2992例患者。Meta分析结果显示：①帕拉米韦组发热时间[MD=1.14,95%Cl（1.11,1.17）]显著低于奥司他韦组;②帕拉米韦组治疗有效率[MD=1.14,95%Cl（1.11,1.17）]显著高于奥司他韦组;③帕拉米韦组不良反应发生率[RR=0.65,95%Cl（0.54,0.79）]显著低于奥司他韦组。药物经济性研究发现,帕拉米韦对比奥司他韦的增量成本-效用比（ICER）为5719.95元,即帕拉米韦每增加1%的平均有效率较奥司他韦需额外花费5719.95元。结论：帕拉米韦在治疗儿童流感的有效性和安全性方面优于奥司他韦,在经济性评价中,以此药“药到病除”,当支付阈值高于5719.95元时,帕拉米韦增加的成本完全值得。