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 after oral administration. After an oral dose of 1200 mg ribavirin, peak plasma concentration (Cmax) is reached in an average of 2 hours. The oral bioavailability of 600 mg ribavirin is 64%. Ribavirin metabolites are excreted via the kidneys. After an oral dose of 600 mg of radiolabeled ribavirin, approximately 61% of the drug is detected in urine and 12% in feces. 17% of the administered dose is excreted unchanged. Ribavirin has a large volume of distribution. The total apparent clearance after a single oral dose of 1200 mg ribavirin is 26 L/h. Ribavirin is systemically absorbed via the respiratory tract after nasal and oral inhalation. The bioavailability of ribavirin administered via nasal and oral inhalation has not been determined but may depend on the nebulization method (e.g., oxygen mask, face mask, oxygen tent). At a constant flow rate, the theoretical amount of drug reaching the respiratory tract is directly related to the concentration of the nebulized drug solution and the duration of inhalation therapy. Furthermore, changes in the aerosol delivery method can also affect the amount of drug reaching the respiratory tract. When using a small-particle aerosol generator for oral and nasal inhalation of a 190 μg/L nebulized ribavirin solution, the estimated average proportion of the inhaled dose deposited in the respiratory tract is approximately 70%, but the actual deposition depends on various factors, including respiratory rate and tidal volume. When using a small-particle aerosol generator for oral and nasal inhalation, peak plasma ribavirin concentrations typically occur at the end of inhalation and increase with prolonged inhalation time. In a small number of pediatric patients, after 3 consecutive days of nasal and oral inhalation at a dose of 0.82 mg/kg/hr via face mask for 2.5 hours, the average peak plasma ribavirin concentration was 0.19 μg/mL (range: 0.11–0.388 μg/mL). In a small number of patients, peak plasma ribavirin concentrations were 0.275 μg/mL (range: 0.21–0.35 μg/mL) or 1.1 μg/mL (range: 0.45–2.18 μg/mL) when administered via 0.82 mg/kg/hour for 5 hours daily via mask, nebulizer tent, or respirator for 20 hours daily. Peak plasma ribavirin concentrations were 1.7 μg/mL (range: 0.38–3.58 μg/mL) when administered via endotracheal inhaler with a given dose of ribavirin. …Peak plasma concentrations of commonly administered ribavirin via nasal and oral inhalation were lower than those reported to reduce respiratory syncytial virus plaque formation by 85–98%.
After patients inhale ribavirin via nasal and oral routes, the concentration of ribavirin in respiratory secretions may be significantly higher than the plasma concentration. In a small number of pediatric patients who received ribavirin via nasal and oral routes for 8 hours daily for 3 consecutive days at a dose of 0.82 mg/kg/hour, the peak drug concentration in respiratory secretions (from endotracheal intubation) ranged from 250 to 1925 μg/mL. In pediatric patients receiving ribavirin via nasal and oral routes for 5 consecutive days for 20 hours daily at a dose of 0.82 mg/kg/hour, the concentration of ribavirin in respiratory secretions (from endotracheal intubation) during treatment ranged from 313 to 28,250 μg/mL, with a mean peak concentration of 3075 μg/mL at the end of treatment (range: 313–7050 μg/mL). The concentrations of ribavirin achieved through nasal and oral inhalation in respiratory secretions may be significantly higher than the concentrations required in vitro to inhibit plaque formation by susceptible strains of respiratory syncytial virus (RSV). However, because RSV exists within cells infected by the respiratory virus, the manufacturer notes that intracellular respiratory drug concentrations are likely more closely related to plasma ribavirin concentrations than to concentrations measured in respiratory secretions. Oral ribavirin is rapidly absorbed, reaching peak plasma concentrations within 1–3 hours after multiple doses. However, due to first-pass metabolism, the absolute bioavailability of oral ribavirin is only about 64% on average. For more complete data on absorption, distribution, and excretion of ribavirin (10 items in total), please visit the HSDB record page. Metabolism/Metabolites: First, and essential for activation, ribavirin is phosphorylated intracellularly by adenosine kinase to produce ribavirin monophosphate, diphosphate, and triphosphate metabolites. After ribavirin is activated and exerts its effect, it undergoes two metabolic pathways: reversible phosphorylation or degradation via deribosylation and amide hydrolysis to produce the triazole carboxylic acid metabolite. In vitro studies have shown that ribavirin is not a substrate of CYP450 enzymes. Ribavirin is primarily metabolized to deribosylated ribavirin (1,2,4-triazole-3-carboxamide), which may occur in the liver; 1,2,4-triazole-3-carboxamide has been reported to have similar antiviral activity against various RNA and DNA viruses as ribavirin. The drug is also metabolized to 1,2,4-triazole-3-carboxylic acid. In vitro studies have shown that ribavirin is primarily phosphorylated intracellularly via adenosine kinase and other cellular enzymes, metabolizing to ribavirin-5'-monophosphate, 5'-diphosphate, and 5'-triphosphate. In vivo phosphorylation is likely a necessary condition for the drug to exert its antiviral activity. Ribavirin is also phosphorylated within erythrocytes, primarily to produce ribavirin-5'-triphosphate. Of the drugs metabolized within erythrocytes, approximately 81%, 16%, and 3% exist as ribavirin-5'-triphosphate, diphosphate, and monophosphate, respectively. Studies have shown that the prolonged distribution of the drug within erythrocytes may be due to the low activity of phosphatases in these cells, and drug transport from cells depends on dephosphorylation by phosphatases. Ribavirin undergoes two metabolic pathways: (i) a reversible phosphorylation pathway occurring in nucleated cells; and (ii) a degradation pathway involving deribosylation and amide hydrolysis, producing triazole carboxylic acid metabolites. Ribavirin, along with its triazole carboxylic acid metabolites, is excreted via the kidneys.
Biological Half-Life
Following a single oral dose of 1200 mg ribavirin, the terminal half-life is approximately 120 to 170 hours.
Distribution: Intravenous injection: approximately 0.2 hours. Elimination: Inhalation: 9.5 hours. Intravenous and oral (single dose): 0.5 to 2 hours. In erythrocytes: 40 days. Terminal half-life: Intravenous and oral: Single dose: 27 to 36 hours. Single oral tablet: 120 to 170 hours. Steady state: Approximately 151 hours. Mean: Multiple oral administration, capsules: 298 hours. Based on limited data, it has been reported that the half-life of ribavirin in respiratory secretions is approximately 1.4–2.5 hours after 3 days of nasal and oral inhalation. In a small number of pediatric patients, the mean plasma half-life of ribavirin after nasal and oral inhalation is approximately 9.5 hours (range: 6.5–11 hours). In a small number of healthy adults, plasma ribavirin concentrations show a multiphasic decline after a single oral dose, with a mean half-life of 24 hours 10–80 hours post-dose and a terminal half-life of 48 hours or longer.

Interactions
Ribavirin's in vitro and in vivo antiviral activity against certain viruses (e.g., influenza virus) may be enhanced by other antiviral drugs (e.g., amantadine, ribavirin). Ribavirin may antagonize the in vitro antiviral activity of stavudine and zidovudine against HIV; concomitant use of ribavirin with these two drugs should be avoided. Oral ribavirin is not recommended for use with dipanosin. Cases of fatal liver failure, peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactal acidosis have been reported in clinical trials. In vitro studies have shown that ribavirin enhances the antiretroviral activity of dipanosin against human immunodeficiency virus (HIV; formerly known as HTLV-III/LAV) and Moroni murine sarcoma virus. Conversely, in vitro studies have shown that ribavirin antagonizes the antiviral activity of zidovudine and zalcitabine against HIV. Ribavirin appears to enhance the antiretroviral activity of didanoxin by promoting the production of didanoxin-S'-triphosphate (the metabolically active metabolite of didanoxin with antiviral activity). The mechanism by which ribavirin antagonizes the antiretroviral activity of zidovudine or zalcitabine is not fully elucidated, but studies suggest that ribavirin may interfere with the phosphorylation steps that convert the drug into its active triphosphate metabolites (deoxythymidine triphosphate and dideoxycytidine-S'-triphosphate, respectively).

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Non-human toxicity values
Oral LD50 in rats: 5.3 g/kg
Oral LD50 in mice: 2 g/kg
Intraperitoneal LD50 in mice: 0.9-1.3 g/kg
Intraperitoneal LD50 in rats: 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

Antimetabolite; Antiviral Drug
Anviral Drug
Ribavirin is used orally and intravenously to treat Lassa fever and as a post-exposure prophylaxis for high-risk contacts. It may also be equally effective against other viral hemorrhagic fevers, including hemorrhagic fever with renal syndrome, Crimean-Congo hemorrhagic fever, and Rift Valley fever. /Not included in the U.S. product label/
Ribavirin inhalation solution is used as adjunctive therapy for the treatment of influenza A and B in young adults, especially when treatment is initiated early in the illness (e.g., within 24 hours of the onset of initial symptoms). /Not included in the U.S. product label/
Ribavirin inhalation solution is used to treat severe lower respiratory tract infections (including bronchiolitis and pneumonia) caused by respiratory syncytial virus (RSV) in hospitalized infants and young children, especially those at risk of severe or complicated RSV infection; such populations include premature infants and infants with structural or physiological cardiopulmonary disease, bronchopulmonary dysplasia, immunodeficiency, or impending respiratory failure. Ribavirin is indicated for the treatment of RSV infection in infants requiring mechanical ventilation. /Included in the US product label/

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Drug Warnings
FDA Pregnancy Risk Category: X /Contraindicated during pregnancy. Animal or human studies, as well as investigational or post-marketing reports, have demonstrated that the risk of fetal malformation or abnormalities significantly outweighs any potential benefit to the patient. /
When deciding whether to treat pediatric patients, evidence of disease progression, such as liver inflammation and fibrosis, as well as prognostic factors, HCV genotype, and viral load should be considered. The treatment benefit should be weighed against the safety outcomes observed in pediatric patients in clinical trials.
Sudden deterioration of respiratory function can sometimes occur in infants receiving ribavirin inhalation (including those with respiratory syncytial virus infection) or adults with chronic obstructive pulmonary disease (COPD) or asthma. In infants with underlying life-threatening conditions, inhalation of this drug has been associated with worsening and deterioration of respiratory function, apnea, and dependence on assisted ventilation. In adults with chronic obstructive pulmonary disease (COPD) or asthma, ribavirin treatment is often accompanied by worsening lung function, with some asthmatic adults experiencing dyspnea and chest pain. Mild lung function abnormalities have also been observed in healthy adults after inhaling ribavirin. Bronchospasm, pulmonary edema, hypoventilation, cyanosis, dyspnea, bacterial pneumonia, pneumothorax, apnea, atelectasis, and ventilator dependence have also been associated with ribavirin inhalation therapy. Some infants have experienced bronchospasm-induced respiratory deterioration during ribavirin treatment, and these deaths have been determined by the treating physician to be possibly related to ribavirin inhalation therapy. Patients receiving ribavirin inhalation therapy may also experience rash, eyelid erythema, and conjunctivitis. These symptoms usually subside within hours of discontinuing ribavirin. In addition, hearing impairment (e.g., hearing loss, tinnitus), dizziness, hypertriglyceridemia, and fatal and non-fatal pancreatitis have been observed in patients receiving ribavirin in combination with interferon alpha-2b. For more complete data on ribavirin (23 in total), please visit the HSDB records page.

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Pharmacodynamics
Ribavirin exerts direct antiviral activity against a variety of DNA and RNA viruses by increasing the mutation frequency of the genomes of various RNA viruses. It belongs to the nucleoside antimetabolite class of drugs and interferes with the replication of viral genetic material. Due to its structural similarity to the building blocks of RNA molecules, this drug inhibits the activity of RNA-dependent RNA polymerase.

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。