Ribavirin disposition in high-risk patients for acquired immunodeficiency syndrome

Laskin, Oscar L.; Longstreth, James; Hart, Catherine C.; Scavuzzo, Donna; Kalman, Concetta M.; Connor, James D.; Roberts, Richard B.

doi:10.1038/clpt.1987.70

Cited by 96 publications

(88 citation statements)

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“…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.…”

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confidence: 70%

“…With the second method of elution (three 0.3-ml volumes of 100 mM formic acid), the sensitivity was 0.4 pM in serum, plasma, and cerebrospinal fluid. Because the sensitivity of the HPLC assay is below the therapeutic levels in serum and plasma reported previously for ribavirin (1, 10,14) and because interassay precision was reduced at ribavirin concentrations of less than 0.5 plM, the precision and recovery studies were performed at ribavirin concentrations of between 0.5 and 50 p.M.…”

Section: Resultsmentioning

confidence: 99%

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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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confidence: 70%

Section: Resultsmentioning

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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“…We conjecture that decreased early plasma RBV levels in SVRs and enhanced hemoglobin declines early in treatment may reflect higher intracellular RBV concentration in SVRs, although this hypothesis will need to be investigated further. Early studies demonstrated that RBV concentration in erythrocytes can vary from 9 to 60 times more than the plasma concentration following multiple twice daily dosing [26,27]. Higher intracellular RBV concentration may translate into increased mutagenic effect, a proposed mechanism of action for RBV, which may act by lowering HCV infectivity [28] thereby leading to an SVR.…”

Section: Discussionmentioning

confidence: 99%

Early ribavirin pharmacokinetics, HCV RNA and alanine aminotransferase kinetics in HIV/HCV co-infected patients during treatment with pegylated interferon and ribavirin

Dahari¹,

Markatou²,

Zeremski³

et al. 2007

Journal of Hepatology

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“…5,6 In contrast to nucleated cells such as hepatocytes, phosphorylation is irreversible in the anucleate erythrocytes, and phosphorylated RBV accumulates because it cannot be exported by the nucleoside carrier. Therefore, the concentration of RBV in erythrocytes is 50-to 70-fold higher than the therapeutic plasma concentration of 9 -15 M. 5,7,8 The high concentration of RBV in erythrocytes is probably responsible for the hemolysis occurring during RBV therapy. A decrease in hemoglobin (HB) is frequently observed in patients who receive RBV, and in one clinical trial this decrease required dose reduction or even treatment discontinuation in 7% of patients.…”

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confidence: 99%

Low membrane protein sulfhydrils but not G6PD deficiency predict ribavirin-induced hemolysis in hepatitis C

et al. 2004

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Hemolysis is a frequent adverse effect of ribavirin (RBV). It has been suggested that oxidative stress plays a role, but mechanisms and predictive risk factors for severe forms remain unknown. Markers of redox status were determined in erythrocytes of 34 patients with hepatitis C-four of them with glucose-6-phosphate-dehydrogenase (G6PD) deficiencybefore and during treatment with RBV and interferon (IFN) and were compared with 10 healthy control subjects. In addition, erythrocytes were incubated with RBV, and the effects of dipyridamole (DPD), diethylmaleate (DEM), and glutathione ester (GSHE) were studied in vitro. Of the 30 patients without G6PD deficiency who were treated with RBV and IFN-␣, five developed major hemolysis (⌬ hemoglobin > 6 g/dL) and 25 developed minor hemolysis (⌬ hemoglobin < 2.5 g/dL). Patients with major hemolysis had lower median pretreatment values of membrane protein sulfhydrils than patients with minor hemolysis (28.4 vs. 36.7 nmol/mg, P < .001). Erythrocytes of G6PD-deficient patients were not more susceptible to RBV-induced hemolysis. In in vitro incubations of erythrocytes, DEM enhanced the RBV-induced decrease of glutathione, protein sulfhydrils, and osmotic resistance. Supplementation of GSHE and DPD prevented the RBV-induced decrease in osmotic resistance, adenosyl triphosphate (ATP), and 2,3-diphosphoglycerate (DPG), the loss of glutathione and protein sulfhydrils, and the formation of thiobarbituric acid reactive substances (TBARs). In conclusion, the data indicate that low membrane protein sulfhydrils prior to therapy but not G6PD deficiency are predictive of RBV-induced major hemolysis. In vitro, GSHE and DPD reduce the RBV-associated oxidative stress in erythrocytes and prevent the increase in osmotic fragility, suggesting that these compounds might decrease the risk of hemolysis in patients. (HEPATOLOGY 2004;39:1248 -1255 R ibavirin (RBV) is a synthetic nucleoside analogue used in the treatment of chronic hepatitis C in combination with interferon (IFN)-␣. The addition of RBV has increased the probability of sustained response to approximately 40% if combined with conventional IFN 1,2 and to over 50% if combined with pegylated IFN. 3 RBV actively enters cells by way of the es-nucleoside membrane transporter 4 and subsequently undergoes phosphorylation at the expense of adenosyl triphosphate (ATP). 5,6 In contrast to nucleated cells such as hepatocytes, phosphorylation is irreversible in the anucleate erythrocytes, and phosphorylated RBV accumulates because it cannot be exported by the nucleoside carrier. Therefore, the concentration of RBV in erythrocytes is 50-to 70-fold higher than the therapeutic plasma concentration of 9 -15 M. 5,7,8 The high concentration of RBV in erythrocytes is probably responsible for the hemolysis occurring during RBV therapy. A decrease in hemoglobin (HB) is frequently observed in patients who receive RBV,

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Ribavirin disposition in high-risk patients for acquired immunodeficiency syndrome

Cited by 96 publications

References 0 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

Early ribavirin pharmacokinetics, HCV RNA and alanine aminotransferase kinetics in HIV/HCV co-infected patients during treatment with pegylated interferon and ribavirin

Low membrane protein sulfhydrils but not G6PD deficiency predict ribavirin-induced hemolysis in hepatitis C

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