Discovery and development of BVDU (brivudin) as a therapeutic for the treatment of herpes zoster.
This Commentary is dedicated to the memory of Dr. Jacques Gielen, the late Editor of Biochemical Pharmacology, whom I have known as both an author and reviewer for the Journal for about 25 years. This is, quite incidentally, about the time it took for bringing brivudin (BVDU) [(E)-5-(2-bromovinyl)-2'-deoxyuridine] from its original description as an antiviral agent to the market place (in a number of European countries, including Germany and Italy) for the treatment of herpes zoster in immunocompetent persons. BVDU is exquisitely active and selective against varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV-1). BVDU owes this high selectivity and activity profile to a specific phosphorylation by the virus-encoded thymidine kinase, followed by a potent interaction with the viral DNA polymerase. The (E)-5-(2-bromovinyl)-substituent can be considered as the hallmark for the activity of BVDU against VZV and HSV-1. Extensive clinical studies have indicated that BVDU as a single (oral) daily dose of 125 mg (for no more than 7 days) is effective in the treatment of herpes zoster, as regards both short-term (suppression of new lesion formation) and long-term effects (prevention of post-herpetic neuralgia). In this sense, BVDU is as efficient and/or convenient, if not more so, than the other drugs (acyclovir, valaciclovir, famciclovir) that have been licensed for the treatment of herpes zoster. There is one caveat; however, BVDU should not be given to patients under 5-fluorouracil therapy, as the degradation product of BVDU, namely (E)-5-(2-bromovinyl)uracil (BVU), may potentiate the toxicity of 5-fluorouracil, due to inhibition of dihydropyrimidine dehydrogenase, the enzyme involved in the catabolism of 5-fluorouracil.
De Clercq
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Department of Microbiology and Immunology, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat B-3000 Leuven, Belgium. erik.declercq@rega.kuleuven.ac.be
D000963:Antimetabolites / Q000494:pharmacology; D000998:Antiviral Agents / Q000627:therapeutic use*; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D004347:Drug Interactions; D005060:Europe; D005472:Fluorouracil / Q000494:pharmacology; D006562:Herpes Zoster / Q000188:drug therapy*; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D014779:Virus Replication / Q000187:drug effects
D000963:Antimetabolites; D000998:Antiviral Agents; C020235:brivudine; D001973:Bromodeoxyuridine; D005472:Fluorouracil