Mitochondrial injury. Lessons from the fialuridine trial.
Fialuridine is an antiviral agent with potent activity against hepatitis B virus replication in vitro and in vivo. In a phase II study, 7 of 15 patients experienced severe toxicity due to the drug after 9 to 13 weeks of treatment. Adverse effects included nausea, vomiting and painful paraesthesia; subsequently, hepatic failure, pancreatitis, neuropathy, myopathy and lactic acidosis developed, probably due to multisystem mitochondrial toxicity. Possible mechanisms of fialuridine toxicity include mitochondrial injury and pyruvate oxidation inhibition. While other nucleoside analogues have shown evidence of inducing mitochondrial injury (zidovudine, didanosine, zalcitabine), others to date have not (lamivudine, famciclovir). Specific recommendations for future study of existing and new nucleoside analogues include testing for toxicity after prolonged incubation, specific investigations to measure mitochondrial function, toxicological tests and well designed clinical trials with appropriate testing to monitor for any adverse effects on mitochondrial integrity and function.
Honkoop
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Department of Internal Medicine II (Section Hepatology), Erasmus University Hospital, Rotterdam, The Netherlands.
Scholte
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HR
de Man
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Schalm
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D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001086:Arabinofuranosyluracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D017322:Clinical Trials, Phase II as Topic; D004259:DNA-Directed DNA Polymerase / Q000187:drug effects / Q000378:metabolism; D006509:Hepatitis B / Q000188:drug therapy*; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D008099:Liver / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010084:Oxidation-Reduction; D011773:Pyruvates / Q000737:chemistry / Q000378:metabolism; D018570:Risk Assessment; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D011773:Pyruvates; D001086:Arabinofuranosyluracil; C043457:fialuridine; D004259:DNA-Directed DNA Polymerase