Ribavirin small-particle aerosol treatment of infections caused by influenza virus strains A/Victoria/7/83 (H1N1) and B/Texas/1/84

Gilbert, Brian E.; Wilson, Samuel Z.; Knight, Vernon; Couch, R B; Quarles, John; Dure, L; Hayes, Ned; Willis, Gabriela A.

doi:10.1128/aac.27.3.309

Cited by 79 publications

(38 citation statements)

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“…It is active in vitro against a wide variety of DNA and RNA viruses (9,18). Controlled in vivo studies have shown that ribavirin is effective against respiratory syncytial virus (8, 16), influenza A and B virus (7), and Lassa fever virus (11) infections. Ribavirin is being studied currently in clinical trials to further evaluate its activity against human immunodeficiency virus infections (5).…”

mentioning

confidence: 99%

High-performance liquid chromatography (HPLC) assay for ribavirin and comparison of the HPLC assay with radioimmunoassay

Granich

Krogstad

Connor

et al. 1989

Antimicrob Agents Chemother

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The use of high-performance liquid chromatography (HPLC) to measure ribavirin in serum and other biological fluids has been limited by endogenous interfering substances. We report an HPLC procedure based on the extraction of ribavirin from serum, plasma, or cerebrospinal fluid with a boronate affinity gel, which uses a 3-methylcytidine internal standard. This assay is sensitive (to 0.4 i,M), specific (no interference with 34 commonly prescribed drugs), reproducible (coefficients of variation from 5.4 to 22.4%), and linear (r = 0.999) over the range of clinically relevant concentrations in serum (from 0.5 to 50.0 ,uM). It also correlates well with the ribavirin radioimmunoassay (r = 0.992). This HPLC assay should be useful for measuring ribavirin in serum and other body fluids during clinical trials.Ribavirin (1-,-D-ribofuranosyl-1,2,4-triazole-3-carboxamide; Virazole) is a purine nucleoside analog which resembles guanosine (13). It is active in vitro against a wide variety of DNA and RNA viruses (9,18). Controlled in vivo studies have shown that ribavirin is effective against respiratory syncytial virus (8, 16), influenza A and B virus (7), and Lassa fever virus (11) infections. Ribavirin is being studied currently in clinical trials to further evaluate its activity against human immunodeficiency virus infections (5). Oral ribavirin also has been employed in the treatment of measles (2) and acute hepatitis A (17) infections.Hematological toxicity, consisting of intravascular erythrocyte losses and reticulocytosis, has been associated with the use of oral ribavirin. Headache, insomnia, fatigue, and exertional dyspnea have been reported in patients receiving large oral or parenteral doses (10,11,14). These and other observations suggest that ribavirin toxicity is dose related and reversible. Sites of toxicity include circulating erythrocytes, the bone marrow, and the central nervous system.Methods available currently for quantitating ribavirin in serum or plasma include bioassay (19), radioimmunoassay (RIA) (1), gas chromatography-mass spectroscopy (15), and high-performance liquid chromatography (HPLC) (3, 20). The use of HPLC to measure ribavirin has advantages over bioassay and gas chromatography-mass spectroscopy in terms of speed (turnaround time) and ease of performance. HPLC does not require the use of radioisotopes, as does the RIA. In this report we describe a rapid, sensitive, and specific HPLC assay for ribavirin in serum, plasma, and cerebrospinal fluid. This technique is potentially applicable to both pharmacokinetic studies and routine clinical assays. A stock solution of ribavirin, corrected for drug potency, was prepared at a concentration of 1.0 mM in distilled water and stored at -70°C until needed. Reference samples containing 0.5, 1.0, 10.0, 30.0, and 50.0 ,uM concentrations of ribavirin were prepared by diluting this stock solution with drug-free pooled human sera. These reference samples were used to assess intrarun and interrun precision. A single calibration standard was prepared in pooled ...

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mentioning

confidence: 99%

High-performance liquid chromatography (HPLC) assay for ribavirin and comparison of the HPLC assay with radioimmunoassay

Granich

Krogstad

Connor

et al. 1989

Antimicrob Agents Chemother

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“…Ribavirin is a broad-spectrum antiviral agent that is used to treat respiratory syncytial virus infections in infants and has been shown to effectively inhibit the replication of influenza, parainfluenza, and a number of other respiratory viruses (7)(8)(9)(10). The current protocol recommends prolonged daily ribavirin treatment periods.…”

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confidence: 99%

Pharmacokinetics of ribavirin aerosol in mice

Gilbert

Wyde

1988

Antimicrob Agents Chemother

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The pharmacokinetics of ribavirin administered in single or multiple treatments to mice by small-particle aerosol were monitored in lung, serum, and brain tissues. Ribavirin aerosol was administered with a standard drug concentration (20 mg/ml) in the reservoir for 12 h or a high dose (60 mg/ml) for 2 or 4 h. After single or 3-day treatments, ribavirin rapidly accumulated in the lungs at concentrations sufficient to inhibit influenza virus or respiratory syncytial virus (1 to 5 mM). While peak levels of ribavirin in the lungs after the high-dose administration were about three times those found with the standard dose, ribavirin was rapidly cleared from the lungs. There was no accumulation of drug in the lungs after multiple treatments. Ribavirin cleared from the lungs was detected in the blood within 15 min. Concentrations in the serum were similar (20 to 30 ,IM) for standard-and high-dose treatments with either single or multiple treatments. Ribavirin clearance from the serum after treatment was similar for each regimen. Ribavirin also rapidly accumulated in the brain to a similar level (ca. 6 nmol per brain) after standard-or high-dose treatment for 3 days. In contrast to ribavirin in the serum, ribavirin in the brain appeared to be slowly cleared, allowing levels to remain relatively constant during and after treatment. With the interest in viral encephalopathies, further evaluation of the possible advantages of this method of drug administration is warranted.Ribavirin is a broad-spectrum antiviral agent that is used to treat respiratory syncytial virus infections in infants and has been shown to effectively inhibit the replication of influenza, parainfluenza, and a number of other respiratory viruses (7-10). The current protocol recommends prolonged daily ribavirin treatment periods. of 12 to 18 h. Recently, we showed that a shorter period of treatment with higher concentrations of ribavirin is as effective in reducing pulmonary viral titers in mice and cotton rats (Sigmoden hispidus) experimentally inoculated with influenza or respiratory syncytial virus and in preventing mortality in mice given lethal doses of influenza A or B virus (18,19). In the present study, the pharmacokinetics of ribavirin in lung, serum, and brain tissues of mice given standard and high doses of ribavirin by continuous small-particle aerosol were monitored by using a high-performance liquid chromatography assay (15) to determine drug levels in these tissues during and after administration. Standard administration consisted of 12 h of drug treatment per day with 20 mg of ribavirin per ml in the reservoir. High-dose, short-duration administration consisted of drug treatment for 2 h twice daily with 60 mg of ribavirin per ml in the reservoir.This report shows that after high-dose, short-duration aerosol administration, ribavirin rapidly accumulated in the lungs and was quickly cleared once treatment had ceased; that ribavirin was quickly absorbed into the blood; and that ribavirin appeared to accumulate in brain tissue. MATERIALS AND ...

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“…A third class of drug being assessed is the inosine monophosphate (IMP) dehydrogenase inhibitors, such as ribavirin. Small controlled studies have shown some efficacy in decreasing fever and influenza A virus shedding when IMP inhibitors are given by aerosol, but no efficacy when given orally [40]. Further study needs to be undertaken to examine the possibility that combinations of the available drugs would increase efficacy.…”

Section: Current Pharmacotherapy and Drug Developmentmentioning

confidence: 99%

Pandemic and seasonal influenza: therapeutic challenges

Memoli

Morens

Taubenberger

2008

Drug Discovery Today

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Influenza A viruses cause significant morbidity and mortality annually, and the threat of a pandemic underscores the need for new therapeutic strategies. Here we briefly discuss novel antiviral agents under investigation, the limitations of current antiviral therapy and stress the importance of secondary bacterial infections in seasonal and pandemic influenza. Additionally, the lack of new antibiotics available to treat increasingly drug resistant organisms such as methicillin-resistant Staphylococcus aureus, pneumococci, Acinetobacter, extended spectrum beta-lactamase producing gram negative bacteria and Clostridium difficile is highlighted as an important component of influenza treatment and pandemic preparedness. Addressing these problems will require a multidisciplinary approach, which includes the development of novel antivirals and new antibiotics, as well as a better understanding of the role secondary infections play on the morbidity and mortality due to influenza infection.

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Ribavirin small-particle aerosol treatment of infections caused by influenza virus strains A/Victoria/7/83 (H1N1) and B/Texas/1/84

Cited by 79 publications

References 8 publications

High-performance liquid chromatography (HPLC) assay for ribavirin and comparison of the HPLC assay with radioimmunoassay

High-performance liquid chromatography (HPLC) assay for ribavirin and comparison of the HPLC assay with radioimmunoassay

Pharmacokinetics of ribavirin aerosol in mice

Pandemic and seasonal influenza: therapeutic challenges

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