Ribavirin   中文名称: 利巴韦林

当用 5、10 和 20 μM 利巴韦林 GMP (ICN-1229) 处理 LPS 刺激的小胶质细胞时，NO2 水平降低了 43% (p<0.05)、53% (p<0.05) 和 59%（ p<0.05）。在非刺激培养物中，利巴韦林 GMP (ICN-1229) (10 mM) 不会显着减少细胞表面积；然而，在 LPS 刺激的小胶质细胞中，它确实显着减少了细胞表面积（32%，p<0.05）[3]。将利巴韦林 GMP (ICN-1229) 与 CM-10-18 组合可减少病毒复制，并且利巴韦林 GMP (ICN-1229) 对 DENV 具有活性，在 A549 细胞中的 EC50 为 3 μM [4]。给予利巴韦林 (20 μM) 7 天后，在源自人 iPSC 细胞的功能性肝细胞样细胞中，丙型肝炎病毒 (HCV) 复制受到抑制 [6]。通过控制与细胞凋亡调节相关的基因，利巴韦林（1、10、25 μg/mL，72 小时）可减少 ZILV 诱导的 hNPC 细胞凋亡，并通过 PI3K/AKT 途径增强生存信号传导 [7]。实时 qPCR[7]

JAT 与干扰素和利巴韦林 GMP (ICN-1229) 联合使用，可显着降低 (p<0.01) ALT、AST 活性和胆红素水平。 JAT、干扰素或利巴韦林 GMP 当与 CCl4 单独给药时，珊瑚似乎对 CCl4 有一定的保肝作用，如无谷物、喂养极差和肝索正常所示。在单独或联合使用 JAT、聚搅拌剂和利巴韦林 GMP (ICN-1229) 治疗组中，TGF-β 和 Bax 表达降低。接受干扰素、利巴韦林 GMP (ICN-1229) 和 JAT 的三联治疗组 p53 表达显着下降 [1]。在血清和脐带水平上，用 400 mg 利巴韦林 GMP (ICN-1229) 胶囊治疗的 Wistar 的激活素 A 显着下降，卵泡抑素大幅增加。利巴韦林 GMP (ICN-1229)：在小鼠中，利巴韦林 GMP（40 mg/kg，口服）与 IFN-α 或 Peg-IFN-α 联合使用时仅显着升高 CM-10，其抗病毒效果为 -18。在培养细胞中，利巴韦林 GMP (ICN-1229) 会降低抗病毒活性 [2]。 DENV病毒感染，同时用单一药物治疗可以减轻病毒警报[4]。

实时 qPCR[7]
细胞类型： hNPC
测试浓度： 1、10、25 μg/ml
孵育时间： 72 小时
实验结果： 与 DMSO 对照处理的细胞相比，BCL2 mRNA 水平增加，BAX mRNA 水平降低。

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蛋白质印迹分析[7]
细胞类型： hNPC
测试浓度： 1、10、25 μg/ml
孵育持续时间：72小时
实验结果：与对照处理的ZIKV感染细胞相比，AKT磷酸化增加。

Absorption, Distribution and Excretion
Ribavirin is reported to be rapidly and extensively absorbed following oral administration. The average time to reach Cmax was 2 hours after oral administration of 1200 mg ribavirin. The oral bioavailability is 64% following a single oral dose administration of 600mg ribavirin.
The metabolites of ribavirin are renally excreted. After the oral administration of 600mg radiolabeled ribavirin, approximately 61% of the drug was detected in the urine and 12% was detected in the feces. 17% of administered dose was in unchanged form.
Ribavirin displays a large volume of distribution.
The total apparent clearance rate after a single oral dose administration of 1200 mg ribavirin is 26L/h.
Ribavirin is absorbed systemically from the respiratory tract following nasal and oral inhalation. The bioavailability of ribavirin administered via nasal and oral inhalation has not been determined but may depend on the method of drug delivery during nebulization (eg, oxygen hood, face mask, oxygen tent). At a constant flow rate, the amount of drug delivered to the respiratory tract theoretically is directly related to the concentration of nebulized drug solution and the duration of inhalation therapy. In addition, alterations in the method of aerosol delivery can affect the amount of drug reaching the respiratory tract. The fraction of an inhaled dose of ribavirin that is deposited in the respiratory tract during oral and nasal inhalation of a nebulized solution containing 190 ug/L using a small particle aerosol generator has been estimated to average about 70%, but the actual amount deposited depends on several factors including respiratory rate and tidal volume.
Peak plasma ribavirin concentrations generally appear to occur at the end of the inhalation period when the drug is inhaled orally and nasally using a small particle aerosol generator, and increase with increasing duration of the inhalation period. Following nasal and oral inhalation (via face mask) of 0.82 mg/kg/hr for 2.5 hr daily for 3 days in a limited number of pediatric patients, peak plasma ribavirin concentrations averaged 0.19 (range: 0.11-0.388) ug/mL. Peak plasma ribavirin concentrations averaged 0.275 (range: 0.21-0.35) or 1.1 (range: 0.45-2.18) ug/mL in a limited number of patients inhaling 0.82 mg/kg per hour for 5 or 8 hr daily, respectively, for 3 days, and averaged 1.7 (range: 0.38-3.58) ug/mL in a limited number of pediatric patients inhaling 0.82 mg/kg per hour via face mask, mist tent, or respirator for 20 hr daily for 5 days. Highest plasma concentrations for a given dosage of ribavirin appear to be achieved in patients receiving the drug from the aerosol generator via an endotracheal tube. ... Peak plasma ribavirin concentrations achieved with nasal and oral inhalation of usual dosages of the drug are less than concentrations that reportedly reduce respiratory syncytial virus plaque formation by 85-98%.
Concentrations of ribavirin achieved in respiratory tract secretions in patients inhaling the drug nasally and orally are likely to be substantially greater than those achieved in plasma. In a limited number of pediatric patients who received a nasally and orally inhaled ribavirin dose of 0.82 mg/kg per hour for 8 hr daily for 3 days, peak concentrations of the drug in respiratory tract secretions (from endotracheal tube) ranged from 250-1925 ug/mL. In pediatric patients who received 0.82 mg/kg per hour via nasal and oral inhalation for 20 hr daily for 5 days, ribavirin concentrations in respiratory tract secretions (from endotracheal tube) ranged from 313-28,250 ug/mL during therapy, with peak concentrations averaging 3075 (range: 313-7050) ug/mL at the end of therapy. Concentrations of ribavirin achieved in respiratory tract secretions via nasal and oral inhalation are likely to be substantially greater than concentrations necessary to inhibit plaque formation of susceptible strains of respiratory syncytial virus in vitro; however, because respiratory syncytial virus is found within virus infected cells in the respiratory tract, the manufacturer states that intracellular respiratory tract drug concentrations may be more closely related to plasma ribavirin concentrations than to those measured in respiratory tract secretions.
Ribavirin is rapidly absorbed following oral administration, with peak plasma concentrations of the drug occurring within 1-3 hr after multiple doses. However, the absolute bioavailability of ribavirin averages only 64% following oral administration because the drug undergoes first-pass metabolism.
For more Absorption, Distribution and Excretion (Complete) data for RIBAVIRIN (10 total), please visit the HSDB record page.

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Metabolism / Metabolites
First and as a step required for activation, ribavirin is phosphorylated intracellularly by adenosine kinase to ribavirin mono-, di-, and triphosphate metabolites. After activation and function, ribavirin undergoes two metabolic pathways where it is reversibly phosphorlyated or degraded via deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite. In vitro studies indicate that ribavirin is not a substrate of CYP450 enzymes.
Ribavirin is metabolized principally to deribosylated ribavirin (the 1,2,4-triazole-3-carboxamide), probably in the liver; the antiviral activity of 1,2,4-triazole-3-carboxamide against various RNA and DNA viruses is reportedly similar to ribavirin. The drug is also metabolized to 1,2,4-triazole-3-carboxylic acid. In vitro, ribavirin has been shown to be metabolized to ribavirin-5'-monophosphate, -diphosphate, and -triphosphate, principally by intracellular phosphorylation of the drug via adenosine kinase and other cellular enzymes. It is likely that phosphorylation in vivo is necessary for the antiviral activity of the drug. Ribavirin also undergoes phosphorylation in erythrocytes, principally to ribavirin-5'-triphosphate; approximately 81, 16, and 3% of drug metabolized in erythrocytes is present as ribavirin-5'-triphosphate, -diphosphate, and -monophosphate, respectively. It has been suggested that prolonged distribution of the drug in erythrocytes may result from minimal phosphatase activity in these cells with transit of the drug out of cells dependent on dephosphorylation via phosphatases.
Ribavirin has two pathways of metabolism: (i) a reversible phosphorylation pathway in nucleated cells; and (ii) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite. Ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are excreted renally.

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Biological Half-Life
The terminal half-life of ribavirin following administration of a single oral dose of 1200 mg is about 120 to 170 hours.
Distribution: Intravenous: Approximately 0.2 hours. Elimination: inhalation: 9.5 hours. Intravenous and oral (single dose): 0.5 to 2 hours. In erythrocytes: 40 days. Terminal: Intravenous and oral: Single dose: 27 to 36 hours. Single oral dose tablet: 120 to 170 hours. Steady state: Approximately 151 hours. Mean :multiple oral dosing, capsule: 298 hours.
Based on limited data, the half-life of ribavirin in respiratory tract secretions following nasal and oral inhalation for 3 days reportedly is approximately 1.4-2.5 hr.
Following nasal and oral inhalation in a limited number of pediatric patients, the plasma half-life of ribavirin averaged about 9.5 (range: 6.5-11) hr. Following oral administration of a single dose of the drug in a limited number of healthy adults, plasma ribavirin concentrations declined in a multiphasic manner, with half-lives averaging 24 hr 10-80 hr after the dose and 48 hr or longer in the terminal phase.

Interactions
In vitro and in vivo antiviral activity of ribavirin against some viruses (eg, influenza virus) may be enhanced by other antiviral agents (eg, amantadine, rimantadine).
Ribavirin may antagonize the in vitro antiviral activity of stavudine and zidovudine against HIV; concomitant use of ribavirin with either of these drugs should be avoided.
Coadministration /of didanosine/ with oral ribavirin is not recommended; cases of fatal hepatic failure, peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials.
Results of in vitro tests in various cell cultures and peripheral blood lymphocytes indicate that ribavirin may potentiate the antiretroviral activity of didanosine against human immunodeficiency virus (HIV; formerly HTLV-III/LAV) and Moloney murine sarcoma virus. Conversely, results of in vitro tests indicate that ribavirin antagonizes the antiviral activity of zidovudine and zalcitabine against HIV. Ribavirin appears to potentiate the antiretroviral effects of didanosine by promoting formation of didanosine-S'-triphosphate, the metabolically active metabolite of didanosine with antiviral activity. The mechanism by which ribavirin antagonizes the antiretroviral effects of zidovudine or zalcitabine has not been elucidated to date but it has been suggested that ribavirin may interfere with phosphorylation steps that convert the drugs to their active triphosphate metabolites, deoxythymidine triphosphate or dideoxycytidine-S'-triphosphate, respectively.

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Non-Human Toxicity Values
LD50 Rat oral 5.3 g/kg
LD50 Mouse oral 2 g/kg
LD50 Mouse ip 0.9-1.3 g/kg
LD50 Rat ip 2 g/kg

[1]. Robert O Baker, et al. Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections. Antiviral Res. 2003 Jan;57(1-2):13-23.
[2]. Abdel-Hamid NM, et al. Synergistic Effects of Jerusalem Artichoke in Combination with Pegylated Interferon Alfa-2a and Ribavirin Against Hepatic Fibrosis in Rats. Asian Pac J Cancer Prev. 2016;17(4):1979-85.
[3]. Refaat B, et al. The effects of pegylated interferon-α and ribavirin on liver and serum concentrations of activin-A and follistatin in normal Wistar rat: a preliminary report. BMC Res Notes. 2015 Jun 26;8:265
[4]. Savic D, et al. Ribavirin shows immunomodulatory effects on activated microglia. Immunopharmacol Immunotoxicol. 2014 Dec;36(6):433-41
[5]. Chang J, et al. Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo. Antiviral Res. 2011 Jan;89(1):26-34
[6]. Sa-Ngiamsuntorn K, et al. A robust model of natural hepatitis C infection using hepatocyte-like cells derived from human induced pluripotent stem cells as a long-term host. Virol J. 2016 Apr 5;13:59.
[7]. Kim JA, Seong RK, Kumar M, Shin OS. Favipiravir and Ribavirin Inhibit Replication of Asian and African Strains of Zika Virus in Different Cell Models. Viruses. 2018 Feb 9;10(2):72.

Therapeutic Uses
Antimetabolites; Antiviral Agents
Antiviral
Oral and intravenous ribavirin are used in the treatment of Lassa fever and as post-exposure prophylaxis in contacts at hgh risk. It may be similarly effective with other viral hemorrhagic fevers, including hemorrhagic fever with renal syndrome, Crimean-Congo hemorrhagic fever, and Rift Valley fever. /NOT included in US product labeling/
Ribavirin inhalation solution is used as a secondary agent in the treatment of influenza A and B in young adults when treatment is started early (eg, within 24 hours of initial symptoms) in the course of the disease. /NOT included in US product labeling/
Ribavirin inhalation solution is for the treatment of severe lower respiratory tract infections (including bronchiolitis and pneumonia) caused by respiratory syncytial virus (RSV) in hospitalized infants and young children who are at high risk for severe or complicated RSV infection; this category includes premature infants and infants with structural or physiologic cardiopulmonary disorder, bronchopulmonary dysplasia, immunodeficiency, or imminent respiratory failure. Ribavirin is indicated in the treatment of RSV infections in infants requiring mechanical ventilator assistance. /Included in US product labeling/

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Drug Warnings
FDA Pregnancy Risk Category: X /CONTRAINDICATED IN PREGNANCY. Studies in animals or humans, or investigational or post-marketing reports, have demonstrated positive evidence of fetal abnormalities or risk which clearly outweights any possible benefit to the patient./
Evidence of disease progression, such as hepatic inflammation and fibrosis, as well as prognostic factors for response. HCV genotype and viral load, should be considered when deciding to treat a pediatric patient. The benefits of treatment should be weighed against the safety findings observed for pediatric patients in clinical trials.
Worsening of respiratory function has occurred, sometimes suddenly, during ribavirin inhalation therapy in infants with RSV infections or in adults with chronic obstructive pulmonary disease (COPD) or asthma. In infants with underlying life-threatening conditions, inhalation of the drug has been associated with aggravation and worsening of respiratory function, apnea, and physical dependence on assisted respiration. In adults with COPD or asthma, therapy with the drug frequently has been associated with deterioration in pulmonary function, and dyspnea and chest soreness have occurred in several adults with asthma. Minor pulmonary function abnormalities have also been observed in healthy adults receiving ribavirin inhalation. Bronchospasm, pulmonary edema, hypoventilation, cyanosis, dyspnea, bacterial pneumonia, pneumothorax, apnea, atelectasis, and ventilator dependence also have been associated with ribavirin inhalation therapy. Several deaths that were characterized as possibly related to ribavirin inhalation therapy by the treating physician occurred in infants who experienced worsening respiratory status related to bronchospasm while receiving the drug.
Rash, erythema of the eyelids, and conjunctivitis have occurred in patients receiving ribavirin inhalation therapy. These effects usually resolve within hours after ribavirin therapy is discontinued. In addition, hearing disorders (e.g., hearing loss, tinnitus), vertigo, hypertriglyceridemia, and fatal and nonfatal pancreatitis have been observed in patients receiving ribavirin in conjunction with interferon alfa-2b.
For more Drug Warnings (Complete) data for RIBAVIRIN (23 total), please visit the HSDB record page.

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Pharmacodynamics
Ribavirin mediates direct antiviral activity against a number of DNA and RNA viruses by increasing the mutation frequency in the genomes of several RNA viruses. It is a member of the nucleoside antimetabolite drugs that interfere with duplication of the viral genetic material. The drug inhibits the activity of the enzyme RNA dependent RNA polymerase, due to its resemblence to building blocks of the RNA molecules.

C8H12N4O5

244.2047

244.08

36791-04-5

Ribavirin;36791-04-5

37542

White to off-white solid powder

2.1±0.1 g/cm3

639.8±65.0 °C at 760 mmHg

174-176°C

340.7±34.3 °C

0.0±2.0 mmHg at 25°C

1.823

-2.26

143.72

4

7

3

17

304

4

C1=NC(=NN1[C@H]2[C@@H]([C@@H]([C@H](O2)CO)O)O)C(=O)N

IWUCXVSUMQZMFG-AFCXAGJDSA-N

InChI=1S/C8H12N4O5/c9-6(16)7-10-2-12(11-7)8-5(15)4(14)3(1-13)17-8/h2-5,8,13-15H,1H2,(H2,9,16)/t3-,4-,5-,8-/m1/s1

1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2,4-triazole-3-carboxamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~100 mg/mL (~409.50 mM)
DMSO : ~100 mg/mL (~409.50 mM)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。