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喂!警惕新型抗病毒药物所致的精神行为异常!

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今天读到《BMJ》11月28日刊登了新闻

News

Japan’s government warns against abnormal behaviour in people taking antivirals for flu

BMJ 2017;359:j5529

doi: https://doi.org/10.1136/bmj.j5529 (Published 28 November 2017)



Local authorities in Japan have been told to take precautions to avoid accidental injury among people with influenza this winter, after the Ministry of Health, Labour, and Welfare reported 54 cases of abnormal behaviour last season among people taking antivirals.

They included two young people who died after jumping from buildings while taking zanamivir (Relenza), the Japan Times reported. In most of the cases—38 of the 54—the drug involved was oseltamivir (Tamiflu).

The suggested precautions included installing extra locks on windows and …


OK,大意就是(综合其他报道):

日本厚生劳动省报告了去年有54例流感患者(主要是儿童和未成年人)服用抗病药物后出现精神行为异常,包括两例儿童服用扎那米韦(Zanamivir)后跳窗死亡。为此厚生劳动省警示当地部门留意以上情况,尤其对以儿童为主的服用抗流感药物的患者,以避免意外损伤。



日本厚生劳动省指出,这类因服用抗流感药物而发生以上四处乱跑并试图跳出窗外的行为异常的报告中,38例是由服用奥司他韦(商品名:达菲)造成,而瑞乐砂引起11例,拉尼米韦5例。为此日本厚生劳动省建议服用这些药物时注意房屋内的门窗已全部关闭严实,有二楼的私宅尽量让流感患者在一楼活动。



既往认为以上副作用以奥司他韦(Oseltamivir,商品名:达菲)为主,但日本已经好几年不给未成年人开具达菲。现在日本厚生劳务省称,服用拉尼米韦(Laninamivir, 主要在日本上市)和扎那米韦(Zanamivir,  商品名:瑞乐砂-Relenza)也会散布同样的风险。 




在流感大爆发时发挥巨大作用的新型抗病毒药物的神经氨酸酶抑制剂的副作用已经开始引人注目了。

神经氨酸酶抑制剂的作用机制用一个简单的比喻就是“瓜熟蒂不落”!


图片来自www.bing.com


如上图最下面的指向右侧水平红箭头所示, 简单地说,就是利用宿主细胞组装完整的子代病毒通过出胞作用离开宿主时,需要神经氨酸酶来水解掉病毒与宿主细胞联结,相当于瓜熟蒂落!——而神经氨酸酶抑制剂的作用恰恰就是抑制住神经氨酸酶,不让这个蒂断开,这样新生病毒就无法漂移出去发挥作用,渐渐死在了宿主细胞的这个蒂上.....


还看不清楚,下面这张够清楚了吧——中间那个红色垂线就是阻止小病毒“独立”的神经氨酸酶抑制剂!


图片来自Nature:https://www.nature.com/articles/nrmicro975




按照可查到的最新的Cochrane数据库的(2014)的系统评价—— 神经氨酸酶抑制剂预防和治疗健康承认及儿童流感的系统评价

Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children.

Cochrane Database Syst Rev. 2014 Apr 10;(4):CD008965. 

doi: 10.1002/14651858.CD008965.pub4.

PMID: 24718923

其结果中对副作用的描述为:Oseltamivir in the treatment of adults increased the risk of nausea (RD 3.66%, 95% CI 0.90 to 7.39); number needed to treat to harm (NNTH) = 28 (95% CI 14 to 112) and vomiting (RD 4.56%, 95% CI 2.39 to 7.58); NNTH = 22 (14 to 42). The proportion of participants with four-fold increases in antibody titre was significantly lower in the treated group compared to the control group (RR 0.92, 95% CI 0.86 to 0.97, I(2) statistic = 0%) (5% absolute difference between arms). Oseltamivir significantly decreased the risk of diarrhoea (RD 2.33%, 95% CI 0.14 to 3.81); NNTB = 43 (95% CI 27 to 709) and cardiac events (RD 0.68%, 95% CI 0.04 to 1.0); NNTB = 148 (101 to 2509) compared to placebo during the on-treatment period. There was a dose-response effect on psychiatric events in the two oseltamivir "pivotal" treatment trials, WV15670 and WV15671, at 150 mg (standard dose) and 300 mg daily (high dose) (P = 0.038). In the treatment of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75 to 10.29); NNTH = 19 (95% CI 10 to 57). There was a significantly lower proportion of children on oseltamivir with a four-fold increase in antibodies (RR 0.90, 95% CI 0.80 to 1.00, I(2) = 0%). .....Oseltamivir increased the risk of headaches whilst on treatment (RD 3.15%, 95% CI 0.88 to 5.78); NNTH = 32 (95% CI 18 to 115), renal events whilst on treatment (RD 0.67%, 95% CI -2.93 to 0.01); NNTH = 150 (NNTH 35 to NNTB > 1000) and nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to 9.51); NNTH = 25 (95% CI 11 to 116).

这里就说到了奥司他韦的主要副作用为:恶心、呕吐、精神效应以及肾脏并发症!

——实际上这是一篇研究者认为“除罗氏和美国食品药物管理局(FDA)之外,唯一基于完整临床报告的达菲疗效独立研究”,由20项奥司他韦(达菲),以及26项扎那米韦(乐感清)的临床试验数据形成。这份报告称,达菲能够显著缓解流感症状,但没有证据表明其能治疗流 感并发症,而肺炎、心肌炎等并发症正是流感造成严重后果的直接因素。换句话说,本研究当年直接引发对奥司他韦疗效的争议,也造成全球各卫生部门为准备应对大流感而大量采购达菲的计划受到了影响!

可以参考:达菲疗效首遭公开质疑 肾损伤等副作用被低估

http://health.sohu.com/20140505/n399143894.shtml



2014年BMJ发表的扎那米韦治疗成人与儿童流感的系统评价中,摘要中几乎没有提及该药的副作用。

Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

BMJ. 2014 Apr 9;348:g2547. 

doi: 10.1136/bmj.g2547.

PMID: 24811412 

最后在正文中找到了对有害副作用的描述—— 简单地说,就是没有增加副作用的风险,恶心、呕吐也很少,而铜也是如此!

In adult treatment trials we found no evidence that zanamivir was associated with an increased risk of reported adverse events. Nausea and vomiting was less frequent in the zanamivir treatment arm...

Data on harms for trials involving children were sparse, and there was no increased risk of adverse events for children randomised to zanamivir...

In harms analysis in prophylaxis trials there was no increased risk of adverse events from zanamivir during the on-treatment phase. 


最后就是最新的有关神经氨酸酶抑制剂的系统评价

Neuraminidase inhibitors for influenza: a systematic review and meta-analysis of regulatory and mortality data.

Health Technol Assess. 2016 May;20(42):1-242. 

doi: 10.3310/hta20420.

PMID: 27246259 

本文非常宏大,结果部分参看网页:

https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0092195/#s2-5

Analysis of harms

Oseltamivir treatment
Nausea, vomiting and diarrhoea

Oseltamivir in the treatment of adults is associated with increased risk of nausea (RR 1.57, 95% CI 1.14 to 2.15; I2 statistic = 43%; RD 3.66%, 95% CI 0.90% to 7.39%; NNTH 28, 95% CI 14 to 112) and vomiting (RR 2.43, 95% CI 1.75 to 3.38; I2 statistic = 12%; RD 4.56%, 95% CI 2.39% to 7.58%; NNTH 22, 95% CI 14 to 42). It is associated with a decreased risk of diarrhoea (RR 0.67, 95% CI 0.46 to 0.98; I2 statistic = 44%; RD 2.33%, 95% CI 0.14% to 3.81%; NNTB 43, 95% CI 27 to 709) compared with placebo during on-treatment periods. Both nausea and vomiting were associated with significant heterogeneity, when treatment effects appeared larger in otherwise healthy adults than in the elderly and the chronically ill. However, one trial of otherwise healthy adults69 also showed smaller effects. Vomiting was more common in those children on oseltamivir treatment than in those on placebo treatment (RR 1.70, 95% CI 1.23 to 2.35; I2 statistic = 0%; RD 5.34%, 95% CI 1.75% to 10.29%; NNTH 19, 95% CI 10 to 57).

Cardiac effects

The cardiac effects of oseltamivir are unclear. Exposure to oseltamivir may reduce cardiac general events compared with placebo (RR 0.49, 95% CI 0.25 to 0.97; I2 statistic = 0%; RD 0.68%, 95% CI 0.04% to 1.00%; NNTB 148, 95% CI 101 to 2509), excluding one trial70 in which electrocardiography was included in the safety parameters. However, exposure to oseltamivir may increase corrected QT interval prolongation (including borderline) as reported in trial WV1627770 (RD 4.0%, 95% CI 0.71% to 7.30%; NNTH 25, 95% CI 14 to 140) compared with placebo during on-treatment periods.

Psychiatric effects

In treatment trials, there was no significant increase in risk between oseltamivir and on-treatment psychiatric adverse events overall (RR 0.93, 95% CI 0.43 to 2.03; I2 statistic = 0%). However, there was a dose–response effect in the two ‘pivotal’ treatment trials.8,58In the identically designed trials8,58 there were two active treatment groups: 150 mg (standard dose) and 300 mg (high dose) oseltamivir per day. In the dose–response analysis there was an increased risk of psychiatric body system adverse events over the entire follow-up period (p = 0.038, based on likelihood ratio test). In one trial,8 the event rates were 1 of 204, 1 of 206 and 4 of 205 in the placebo, 75-mg and 150-mg arms, respectively, whereas the second trial58 had rates of 2 of 235, 0 of 242 and 5 of 242, respectively.

Effect on antibodies (post-protocol hypotheses)

The proportion of patients being diagnosed as influenza infected in oseltamivir treatment of adults was significantly lower in the treated group than in the control group (RR 0.95, 95% CI 0.91 to 0.99; I2 statistic = 0%). The proportion of patients with fourfold increases in antibody titre was significantly lower in the treated group than in the control group (RR 0.92, 95% CI 0.86 to 0.97; I2statistic = 0%). This represents an absolute difference of 5% between treatment groups. There was a lower proportion of children on oseltamivir with a fourfold increase in antibodies (RR 0.90, 95% CI 0.80 to 1.00; I2 statistic = 0%).

Oseltamivir prophylaxis
Headaches and nausea

In oseltamivir prophylaxis, there was an increased risk of headaches on-treatment (RR 1.18, 95% CI 1.05 to 1.33; I2 statistic = 0%; RD 3.15%, 95% CI 0.88% to 5.78%; NNTH 32, 95% CI 18 to 115) (Figure 8) and nausea on-treatment (RR 1.96, 95% CI 1.20 to 3.20; I2 statistic = 49%; RD 4.15%, 95% CI 0.86% to 9.51%; NNTH 25, 95% CI 11 to 116). There was also a dose–response effect for headaches in study52 (p = 0.013, based on likelihood ratio test), for which on-treatment rates were 202 of 519, 225 of 520 and 242 of 520 in the placebo, standard-dose and high-dose arms, respectively.

Psychiatric effects

Figure 9 shows that in prophylaxis trials of oseltamivir there was a significant increase in patients with psychiatric adverse events over the on- and off-treatment periods (RR 1.80, 95% CI 1.05 to 3.08; I2 statistic = 0%; RD 1.06%, 95% CI 0.07% to 2.76%; NNTH 94, 95% CI 36 to 1538). Initial analysis of patients with psychiatric adverse events in the on-treatment period showed a borderline statistically significant result (p = 0.06), hence we conducted sensitivity analysis using Peto’s method (p = 0.05) as well as the analysis reported in Figure 9.

Table 14 shows a summary of all of the psychiatric adverse events in oseltamivir prophylaxis trials. Of particular note was an oseltamivir patient in one study68 who had severe confusion on day 27 and was hospitalised. On day 28 the patient was taken off medication and the event resolved. On day 29 the patient was discharged from hospital and subsequently resumed medication. However, confusion reappeared on day 32. The initial event was misclassified in the CSR as ‘mental impairment’ but has since been corrected in an erratum published in the same journal that published the original trial manuscript.37,38

Renal effects

There was a non-significant increase in renal events on-treatment (RR 3.17, 95% CI 0.96 to 10.49; I2 statistic = 0; RD 0.67%, 95% CI –0.01% to 2.93%; NNTH 150, 95% CI NNTH 35 to ∞ to NNTB > 1000). However, in sensitivity analysis using Peto’s method the result for renal events was statistically significant (p = 0.02).

Zanamivir
Serious adverse events

There was no significant effect on serious adverse events in adult treatment trials (RR 0.86, 95% CI 0.49 to 1.50; I2 statistic = 0%).

Nausea, vomiting and diarrhoea

In treatment trials, there was no significant effect on diarrhoea in adults (RR 0.87, 95% CI 0.66 to 1.14; I2 statistic = 5%) or headache (RR 0.84, 95% CI 0.60 to 1.18; I2 statistic = 0). However, during the on-treatment phase, nausea and vomiting were significantly less frequent in the zanamivir arm (RR 0.60, 95% CI 0.39 to 0.94; I2 statistic = 0%; RD 1.63%, 95% CI 0.24% to 2.48%; NNTB 62, 95% CI 41 to 411).

Renal, psychiatric and other harms

There was no significant effect observed on the renal system (RR 0.84, 95% CI 0.41 to 1.72; I2 statistic = 0%) or the psychiatric system (RR 1.16, 95% CI 0.57 to 2.38; I2 statistic = 0%). In adult treatment trials of zanamivir, there was no significantly increased risk of any other reported adverse events, and there was no significant increase in adverse effects observed in prophylaxis trials, including psychiatric (RR 1.05, 95% CI 0.48 to 2.29; I2 statistic = 25%) and renal effects (RR 0.67, 95% CI 0.35 to 1.26; I2 statistic = 0%) on-treatment. There was no significant increase in harms associated with zanamivir treatment of children but data were sparse.

Effect on antibodies

There was no significant effect of zanamivir treatment on influenza diagnosis (RR 1.02, 95% CI 0.98 to 1.06; I2 statistic = 0%) or probability of a fourfold increase in antibody titre (RR 1.06, 95% CI 0.96 to 1.06; I2 statistic = 0%).

Deaths

In oseltamivir treatment trials, there was one death overall. This event occurred as a result of acute respiratory syndrome in a placebo patient without influenza in study.66 In prophylaxis trials, there were four deaths in total, all in elderly patients, with two in the placebo group and two in the oseltamivir group. Causes of death were reported as two cancers, one myocardial infarction and one intestinal perforation. However, for both deaths in the oseltamivir arms the participants experienced acute renal failure on-treatment prior to death.

There were eight deaths in total in the zanamivir trials. Six of the deaths were caused by neoplasias or cardiovascular events in elderly patients with multiple pathologies. However, two deaths were reported as being due to influenza A pneumonia. One participant was on inhaled rimantadine plus placebo and the other on zanamivir.


看来在文献中,这几种药物的副作用主要是增加消化系统的症状,神经系统和肾脏的副作用虽有,但几乎均为特殊提及,尤其是行为异常更未引起足够的注意——不过,仔细看上面的表14中,能够发现奥司他韦与对照组精神症状有显著差异或接近显著差异的就有Hallucinations(幻觉)、Psychosis(精神错乱)、Schizophrenia(精神分裂症)、Bipolar disorder(躁郁症)、Aggression( 攻击性)、Restlessness(躁动)、Nervousness(神经质)、Suicide ideation(意念)、Paranoia(妄想狂),可见这些精神行为异常还是应当高度警惕的——无论成人还是儿童!


好了今天就到这里吧,晚安!




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