Potential of Arbidol for Post-exposure Prophylaxis of COVID-19 Transmission:A Preliminary Report of a Retrospective Cohort Study

The efficient transmission of severe acute respiratory syndrome-2 coronavirus(SARS-CoV-2)from patients to health care workers or family members has been a worrisome and prominent feature of the ongoing outbreak.On the basis of clinical practice and in-vitro studies,we postulated that post-exposure prophylaxis(PEP)using Arbidol is associated with decreased infection among individuals exposed to confirmed cases of COVID-19 infection.We conducted a retrospective cohort study on family members and health care workers who were exposed to patients confirmed to have SARS-CoV-2 infection by real-time RT-PCR and chest computed tomography(CT)from January 1 to January 16,2020.The last follow-up date was Feb.26,2020.The emergence of fever and/or respiratory symptoms after exposure to the primary case was collected.The correlations between post-exposure prophylaxis and infection in household contacts and health care workers were respectively analyzed.A total of 66 members in 27 families and 124 health care workers had evidence of close exposure to patients with confirmed COVID-19.The Cox regression based on the data of the family members and health care workers with Arbidol or not showed that Arbidol PEP was a protective factor against the development of COVID-19(HR 0.025,95%CI 0.003-0.209,P=0.0006 for family members and HR 0.056,95%CI 0.005-0.662,P=0.0221 for health care workers).Our findings suggest Arbidol could reduce the infection risk of the novel coronavirus in hospital and family settings.This treatment should be promoted for PEP use and should be the subject of further investigation.

Efficacy of arbidol in COVID-19 patients:A retrospective study

To date,no treatment has proven to be absolutely effective for coronavirus disease 2019(COVID-19)patients,and further research is necessary.As a traditional antiviral drug,arbidol was widely used in Wuhan at the beginning of the COVID-19 epidemic and is of increasing interest for treating COVID-19 based on in vitro data suggesting activity against severe acute respiratory syndrome(SARS).Although arbidol has been widely used in China to treat COVID-19 patients,clinical trials to date have not clearly substantiated this approach.AIM To evaluate the efficacy of arbidol for COVID-19.METHODS A retrospective study was conducted on 132 moderate and severe COVID-19 patients admitted to Jinyintan Hospital and Huoshenshan Hospital(officially designated for COVID-19 treatment)from February to March 2020 in Wuhan,China.This study mainly evaluated the efficacy of arbidol in patients with COVID-19 in the early stage of the SARS coronavirus 2 epidemic.Arbidol was administered at a dose of 200 mg,three times a day,with a 10-d course to adults not receiving any other drugs.Due to the shortage of beds at the time,not every patient could be admitted immediately.We looked for the early stages of the sudden outbreak,places of limited medical resources,limited ward beds,and delayed admission;thus,some patients naturally fit into the control group who did not receive any antiviral drugs.Out of the 132 patients,72 received arbidol treatment,and 60 did not.We compared the disease course of the two groups and explored the predictors of extended disease duration.RESULTS Seventy-two patients commenced arbidol,and 60 patients did not receive arbidol treatment.The disease duration in the former group was shorter(23.42±6.92 vs 29.60±6.49,P<0.001).Multivariate regression analysis showed that the risk of a prolonged course of disease increased by 7.158 times in the non-arbidol treatment group.Ferritin>483.0 ng/mL and lactate dehydrogenase(LDH)>237.5 U/L were found to be independent risk factors for protracted cases,with the risk of an extended disease duration increasing to 2.852 times and 5.946 times,respectively.CONCLUSION The duration course of moderate and severe COVID-19 patients is reduced by 6.183 d when arbidol is administered.Ferritin>486.5 ng/mL and LDH>239.5 U/L are independent risk factors for delayed recovery from COVID-19.Early oral administration of arbidol 200 mg t.i.d.with a 10-d course of treatment may be an effective management strategy in COVID-19 patients,particularly those with increased serum ferritin or elevated LDH.

Preparation and evaluation of taste masked oral suspension of arbidol hydrochloride

The purpose of this study was to cover the bitter taste of arbidol hydrochloride(ARB)and develop dry suspension with combination of solid dispersion and flavors.Taste masking was successfully done by solid dispersion using octadecanol as the carrier by fusion method.Suspending agents,carriers and other excipients were selected.Differential scanning calorimetry(DSC)and Fourier transform infrared spectroscopy(FTIR)were performed to identify the physicochemical interaction between drug and carrier,DSC analysis indicated that ARB was amorphous in the solid dispersion,FTIR spectroscopy showed no interaction between drug and carrier.Taste masking was evaluated on six volunteers with a score of 4.9.The results demonstrated successful taste masking.Water was used to study the in vitro dissolution performance of the three formulations of commercial tablet,capsule and self-made suspension.The self-made suspension showed a lower and slower release,the insoluble carrier octadecanol blocked the drug dissolving from the solid dispersion.It was indicated from the primary stability study,the self-made suspensions were sensitive to high temperature,high humidity and strong light conditions,they should be stored in sealed containers away from heat,light and humidity.

Prolonged SARS-CoV-2 Viral Shedding in Patients with COVID-19 was Associated with Delayed Initiation of Arbidol Treatment and Consulting Doctor Later: A Retrospective Cohort Study

Objective:To study data about SARS-CoV-2 virus shedding and clarify the risk factors for prolonged virus shedding.Methods:Data were retrospectively collected from adults hospitalized with laboratory-confirmed coronavirus disease-19(COVID-19)in Wuhan Union Hospital.We compared clinical features among patients with prolonged(a positive SARS-CoV-2 RNA on day 23 after illness onset)and short virus shedding and evaluated risk factors associated with prolonged virus shedding by multivariate regression analysis.Results:Among 238 patients,the median age was 55.5 years,57.1%were female,92.9%(221/238)were administered with arbidol,58.4%(139/238)were given arbidol in combination with interferon.The median duration of SARS-CoV-2 virus shedding was 23 days(IQR,17.8-30 days)with a longest one of 51 days.The patients with prolonged virus shedding had higher value of D-dimer(P=0.002),IL-6(P<0.001),CRP(P=0.005)and more lobes lung lesion(P=0.014)on admission,as well as older age(P=0.017)and more patients with hypertension(P=0.044)than in those the virus shedding less than 23 days.Multivariate regression analysis revealed that prolonged viral shedding was significantly associated with initiation arbidol≥8 days after symptom onset[OR:2.447,95%CI(1.351-4.431)],≥3 days from onset of symptoms to first medical visitation[OR:1.880,95%CI(1.035-3.416)],illness onset before Jan.31,2020[OR:3.289,95%CI(1.474-7.337)].Arbidol in combination with interferon was also significantly associated with shorter virus shedding[OR:0.363,95%CI(0.191-0.690)].Conclusion:Duration of SARS-CoV-2 virus shedding was long.Early initiation of arbidol and arbidol in combination with interferon as well as consulting doctor timely after illness onset were helpful for SARS-CoV-2 clearance.

Efficacy and safety of the combination of Liushen capsules and Arbidol in the treatment of COVID-19:protocol for a randomized,multi-center pilot study

Background:From early experience,some Traditional Chinese Medicine and Arbidol had effects of against COVID-19,infer that the combination of Liushen capsules and Arbidol may further increase the therapeutic.Methods/Design:We conducted a randomized,blank parallel-controlled,open-label,multi-center,basal therapy-loaded design clinical trial.A total of 40 patients are going to be recruited after satisfying the criteria.Participants will be allocated randomly into the treatment group with the combination of Arbidol and Liushen capsules and the control group with the basic therapy.Each group will receive treatment at least 7-days or until the virus becomes negative,and visits after drug administration at day 3(visit 1),the day when the virus becomes negative(visit 2),day 7(visit 3),the day before discharge(visit 4)and day 28(visit 5),to collect their survival status and disease prognosis so that the efficacy and safety of a combination of Arbidol and Liushen capsule will be evaluated.Discussion:We described the protocol of the first clinical trial for treatment COVID-19 by using a combination of Arbidol and Liushen capsules.The results of this study will provide a basis for the design and sample size estimate of subsequent large-scale clinical trials.Trial registration:This study has been registered at Chinese clinical trial Registry(chictr.org.cn):ChiCTR2000029993.

Atrial of arbidol hydrochloride in adults with COVID-19

Background: To date, there is no effective medicine to treat coronavirus disease 2019 (COVID-19), and the antiviral efficacy of arbidol in the treatment for COVID-19 remained equivocal and controversial. The purpose of this study was to evaluate the efficacy and safety of arbidol tablets in the treatment of COVID-19.Methods: This was a prospective, open-label, controlled and multicenter investigator-initiated trial involving adult patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients were stratified 1:2 to either standard-of-care (SOC) or SOC plus arbidol tablets (oral administration of 200 mg per time, three times a day for 14 days). The primary endpoint was negative conversion of SARS-CoV-2 within the first week. The rates and 95% confidential intervals were calculated for each variable.Results: A total of 99 patients with laboratory-confirmed SARS-CoV-2 infection were enrolled;66 were assigned to the SOC plus arbidol tablets group, and 33 to the SOC group. The negative conversion rate of SARS-CoV-2 within the first week in patients receiving arbidol tablets was significantly higher than that of the SOC group (70.3% [45/64]vs. 42.4% [14/33];difference of conversion rate 27.9%;95% confidence interval [CI], 7.7%-48.1%;P=0.008). Compared to those in the SOC group, patients receiving arbidol tablets had a shorter duration of clinical recovery (median 7.0 daysvs. 12.0 days;hazard ratio [HR]: 1.877, 95% CI: 1.151-3.060,P=0.006), symptom of fever (median 3.0 daysvs. 12.0 days;HR: 18.990, 95% CI: 5.350-67.410,P<0.001), as well as hospitalization (median 12.5 daysvs. 20.0 days;P<0.001). Moreover, the addition of arbidol tablets to SOC led to more rapid normalization of declined blood lymphocytes (median 10.0 daysvs. 14.5 days;P > 0.05). The most common adverse event in the arbidol tablets group was the elevation of transaminase (5/200, 2.5%), and no one withdrew from the study due to adverse events or disease progression.Conclusions: SOC plus arbidol tablets significantly increase the negative conversion rate of SARS-CoV-2 within the first week and accelerate the recovery of COVID-19 patients. During the treatment with arbidol tablets, we find no significant serious adverse events.

基于转录组学探讨阿比朵尔对HCoV-OC43感染诱导神经营养因子信号通路活化的影响

目的采用转录组学技术分析阿比多尔(arbidol,ARB)对HCoV-OC43感染引起宿主信号通路活化的影响,并探讨ARB抗炎活性与其作用于神经营养因子信号通路的关系。方法用OC43感染HRT-18细胞,并以ARB进行干预。感染96 h后提取总RNA,进行转录组学分析,获得差异表达基因(differentially expressed genes,DEGs),开展基因本体(GO)和京都基因与基因组百科全书(KEGG)富集分析,筛选出ARB可能作用的生物学过程及相关信号通路。进一步利用RT-qPCR方法验证ARB干预对神经营养因子信号通路关键分子表达的抑制作用。结果与病毒感染组相比,高、中和低剂量(6、2和0.67μg/mL)ARB干预分别显示出9459、4186和1744个DEGs。GO分析显示,ARB主要干预的生物学过程是共翻译蛋白膜靶向,作用的细胞组成为粘着斑和细胞-底物间连接,影响的分子功能为钙粘蛋白结合。KEGG分析发现,与冠状病毒感染相关的细胞凋亡信号通路和神经营养因子信号通路有明显富集,其中ARB对神经营养因子信号通路中的MAPK、PI3K和NF-κB通路分子有显著抑制作用。RT-qPCR检测显示,ARB对PIK3CA、AKT、TRAF-6、Bax、p38和c-JUN等分子的mRNA表达具有明显抑制作用。结论本研究提示了ARB应用于治疗冠状病毒感染引起神经炎症的可能性。

阿比朵尔治疗流行性感冒的随机、双盲、安慰剂对照、多中心临床研究

目的验证盐酸阿比朵尔在中国自然获得流行性感冒受试者中的临床疗效并观察其安全性和耐受性。方法采用随机、双盲和安慰剂对照的多中心临床试验设计。共入组232人,入组条件为年龄≥18岁,≤65岁;发热≥37.8℃;符合流感疑似病例诊断标准;出现症状后不超过36h。合格的受试者随机接受盐酸阿比朵尔200mg或安慰剂治疗,每日3次,共5d。结果疗效分析总体为PPi,即指按规定服用药物并完成所有随访且实验室检查证明为流感病毒感染的病例,试验组59例,对照组66例。两组疾病缓解率经生存分析Logrank检验,试验组缓解率高于对照组。试验组疾病持续时间中位数为72.00h(95%可信区间为66.00～78.00h),对照组疾病持续时间中位数为96.00h(95%可信区间为87.46～104.54h),两组比较差异有显著性(P=0.0083)。试验组症状总分下降值的曲线下面积中位数为780.00(95%可信区间为700.77～859.23),对照组中位数为684.00(95%可信区间为559.81～808.19),两组经Wilcoxon检验差异有显著性(P=0.005)。共有232例可用于安全性分析熏试验组113例,对照组119例。共有20例不良事件可能与研究药物有关,其中试验组7例(6.19%),对照组13例(10.9%),两组间差异无显著性(P=0.245)。不良反应主要为消化系统症状和血清转氨酶升高。结论盐酸阿比朵尔在流感发病?

阿比朵尔人血浆蛋白结合率的测定

目的:建立测定阿比朵尔血浆药物浓度的高效液相色谱法(HPLC),并考察阿比朵尔的人血浆蛋白结合率。方法:采用平衡透析法结合HPLC,对阿比朵尔的人血浆蛋白结合率进行测定。结果:低、中、高3种浓度下,阿比朵尔的血浆蛋白结合率分别为90．1％,91．1％和89．8％。结论:本方法灵敏度高,重现性好,操作简单,能满足药品分析要求。阿比朵尔与血浆蛋白具有较强的结合。

盐酸阿比朵尔抗流感病毒感染的药效学研究

目的 探讨盐酸阿比朵尔的抗流感病毒作用。方法 建立体内、体外流感病毒模型 ,体外实验为应用一定浓度盐酸阿比朵尔作用于甲型流感病毒H1N1亚型病毒感染宿主细胞 ,通过观察CPE及采用MTT法测定细胞存活率 ;体内实验为应用盐酸阿比朵尔治疗流感病毒感染小鼠模型 ,计算肺指数的变化。结果 盐酸阿比朵尔在体内、体外均具有明显的抗流感病毒作用。结论 盐酸阿比朵尔是一种较好的抗流感病毒药物。

盐酸阿比朵尔片治疗流行性感冒的多中心随机双盲平行对照临床研究

目的研究盐酸阿比朵尔片(抗感冒药)治疗流行性感冒的疗效和安全性。方法用多中心随机双盲平行对照试验设计,随机分为试验组(108例)与对照组(105例),2组分别口服盐酸阿比朵尔片或利巴韦林片每次0.2g,疗程共6天。结果2组临床总效率(91.67%vs82.86%)和痊愈率(82.41%vs73.33%)比较均无显著性差异(PP分析,P>0.05);症状总改善率中位数均达100%。2组药物不良反应发生率(7.62%vs5.71%)比较无显著性差(P>0.05)。结论在流感发病早期,用盐酸阿比朵尔片可缩短疾病持续时间,减轻症状,且耐受性较好。

阿比多尔抗SARS病毒的体外实验研究

目的 观察抗流感病毒药物阿比多尔 (arbidole)体外抗SARS -CoV作用。方法 以利巴韦林作为阳性对照药 ,采用MTT法和细胞病变 (CPE)法 ,观察阿比多尔对SARS -CoV的抑制作用。结果 MTT法测得阿比多尔对细胞的最大无毒浓度为10 μg·ml-1,对SARS -CoV的IC50 为 7.14 μg·ml-1,治疗指数TI为 1.77。阳性对照药利巴韦林的IC50 为 6 6 .1μg·ml-1,治疗指数TI>6 .1。结论 阿比多尔在体外对SARS -CoV有抑制作用。

阿比朵尔对小鼠的免疫调节作用

目的观察阿比朵尔(Ar)对小鼠的干扰素诱导和免疫调节作用. 方法观察3种剂量Ar灌胃对正常小鼠不同时间血清干扰素(IFN)含量的影响,对正常小鼠腹腔巨噬细胞吞噬百分率和吞噬指数、对氢化可的松(Hc) 形成免疫功能低下小鼠的碳廓清指数和迟发型超敏反应、对正常和环磷酰胺(Cy)所致免疫低下小鼠血清溶血素含量的影响.结果小鼠给予Ar后6～24 h,血清中均出现INF,高峰在用药后18 h.Ar灌胃5 d使正常小鼠腹腔巨噬细胞吞噬功能增强,使免疫低下小鼠碳廓清指数和迟发型超敏反应增强,使正常小鼠和免疫低下小鼠血清溶血素含量升高.结论 Ar对小鼠具有明显的体内诱生干扰素作用,对正常和免疫低下小鼠的非特异性免疫功能、体液和细胞免疫功能具有增强作用.

盐酸阿比朵尔的合成

以对苯醌、3-氨基巴豆酸乙酯经Nenitzescu反应、O-酰化、N-甲基化制得关键中间体5-乙酰氧基-1,2-二甲基-1H-吲哚-3-羧酸乙酯,再经溴代、缩合、Mannich反应合成目标化合物,总收率22.9%。

盐酸阿比朵尔抗腺病毒7型的实验研究

目的:明确抗病毒新药盐酸阿比朵尔体外抗腺病毒7型(ADV-7)的作用方式。方法:主要通过观察细胞病变效应(CPE)、噻唑蓝(MTT)比色法检测细胞活性、病毒滴定3种方法从药物抗病毒生物合成、药物直接杀伤病毒以及药物抗病毒吸附3方面检测盐酸阿比朵尔的作用方式。结果:盐酸阿比朵尔对ADV-7无直接杀伤作用,也不能阻止ADV-7的吸附和穿入,各用药组均出现典型的CPE,但盐酸阿比朵尔能明显抑制ADV-7的生物合成作用,对细胞的半数毒性浓度(CC50)为85.37 mg/L,对ADV-7的半数有效浓度(IC50)为15.39 mg/L,治疗指数(TI)为5.55,且随着药物浓度的增加,病毒所致的CPE效应逐渐减弱,培养液中的病毒滴度也逐渐降低,而病毒抑制率则明显升高。结论:盐酸阿比朵尔在体外通过抑制病毒生物合成而发挥抗ADV-7的作用,其具体作用机制有待进一步研究。

盐酸阿比朵尔胶囊剂、片剂在中国健康人体药动学和相对生物利用度

目的研究盐酸阿比朵尔胶囊剂、片剂与参比胶囊剂相对生物等效性。方法24名健康志愿者按拉丁方设计分成3组,单剂量三交叉po600mg盐酸阿比朵尔胶囊剂、片剂或参比制剂。用高效液相色谱法检测血浆中阿比朵尔的浓度,计算3种制剂的药动学参数及相对生物利用度,并进行生物等效性评价。结果3者的实测tmax分别为(1.74±0.86),(1.60±1.22)和(1.66±1.21)h,实测ρmax分别为(1031.24±405.55),(1101.32±530.17)和(1143.25±635.86)μg·L-1。梯形法计算AUC0-t分别为(7653.93±2880.87),(8087.31±3162.71)和(8126.53±3911.13)μg·h·L-1。t1/2分别为(13.10±4.13),(13.00±3.97)和(13.80±4.30)h。盐酸阿比朵尔胶囊剂、片剂的相对生物利用度分别为(99.1±21.5)%,(105.8±39.8)%。结论经统计学分析,3者具有生物等效性。

阿比多尔联合连花清瘟胶囊治疗新型冠状病毒肺炎的临床观察

目的探讨阿比多尔联合连花清瘟胶囊治疗新型冠状病毒肺炎(COVID-19)的疗效及安全性。方法回顾分析32例COVID-19患者的临床资料,分为A+L组18例和L组14例。A+L组予阿比多尔联合连花清瘟胶囊治疗,L组予单纯服用连花清瘟胶囊治疗。统计患者住院期间主要临床干预措施的使用例数及比例,记录住院期间的临床结局,统计各观察指标及肝功能异常率。结果两组治疗过程中转成危重症病例各1例。A+L组肝功能异常14例(77.78%),L组8例(57.14%)。A+L组使用抗菌药物17例(94.44%),L组13例(92.86%)。A+L组使用糖皮质激素10例(55.56%),L组9例(64.29%)。与L组比较,A+L组的体温恢复正常时间(t=-2.471,P=0.019)、呼吸道症状明显好转时间(t=-2.918,P=0.007)、胸部CT显示炎症明显吸收时间(t=-2.937,P=0.006)、连续2次病毒核酸转阴时间(t=-2.930,P=0.006)、住院时间(t=-2.785,P=0.009)均显著缩短,差异有统计学意义。结论阿比多尔联合连花清瘟胶囊可用于COVID-19患者的治疗,耐受性良好,能够有效缩短患者住院时间及治疗时间,值得临床推广。

盐酸阿比朵尔微乳的制备及其质量评价

目的:研制阿比朵尔微乳并对其质量进行评价。方法:选用肉豆蔻酸异丙酯作为油相,蓖麻油聚氧乙烯醚-40、聚山梨酯-20和聚山梨酯80-司班20(质量比为49∶51)分别作为表面活性剂,乙醇、正丁醇和异丙醇作为助表面活性剂。再通过滴定法制备伪三元相图的基础上,根据相图优选处方,分别考察微乳制剂的稳定性、形态粒径;用高效液相色谱(HPLC)法测定微乳中阿比朵尔的含量。结果:以蓖麻油聚氧乙烯醚-40为表面活性剂和乙醇作为助表面活性剂形成微乳系统。阿比朵尔微乳稳定,透射电镜下呈圆球形,分布均匀,平均粒径为28.4nm,呈Gauss分布。用RP-HPLC法测定回收率为100.18%,RSD为0.51%(n=6)。结论:采用微乳作为药物载体制备口服阿比朵尔微乳,为开发阿比朵尔微乳新型口服制剂提供了依据;HPLC检测方法可靠,重复性好。

盐酸阿比朵尔颗粒剂、干混悬剂与胶囊剂在健康人体的相对生物利用度

目的研究盐酸阿比朵尔(抗流感病毒药)颗粒剂、干混悬剂与胶囊剂的生物等效性。方法24名健康志愿者按拉丁方设计分成3组,用自身交叉对照单剂口服盐酸阿比朵尔颗粒剂、干混悬剂或胶囊剂600mg。用高效液相色谱法检测血浆中盐酸阿比朵尔的浓度,计算3种制剂的药代动力学参数及相对生物利用度,并进行生物等效性评价。结果3者的tmax分别为(0.88±0.46),(0.77±0.29),(1.35±0.97)h;Cmax分别为(1.15±0.53),(1.21±0.43),(1.04±0.47)μg.mL-1;AUC0-t分别为(7.02±2.94),(6.96±2.65),(6.90±2.56)μg.h.mL-1。盐酸阿比朵尔颗粒剂、干混悬剂的相对生物利用度分别为(102.3±19.5)%,(103.3±25.8)%。结论3者具有生物等效性。

盐酸阿比朵尔安全性药理研究

目的:观察盐酸阿比朵尔对中枢神经系统、心血管系统和呼吸系统的影响。方法:观察ig给予盐酸阿比朵尔(10,50和250mg·kg^(-1))对小鼠大体行为、翻正反射、自主活动、感觉和记忆功能、睡眠诱导的影响;观察ig给予盐酸阿比朵尔(10,30和90mg·kg^(-1))对家兔体温变化的影响;观察ig给予盐酸阿比朵尔(20和80mg·kg^(-1))对麻醉犬的呼吸频率和幅度、收缩压和舒张压、心率及心律、心电图的QRS波、T波、ST段和PR间期的影响。结果:小鼠ig盐酸阿比朵尔(250mg·kg^(-1))有协同戊巴比妥钠睡眠诱导作用外,其余指标均无明显影响。结论:盐酸阿比朵尔对中枢神经系统、心血管系统和呼吸系统均无影响。