Idoxuridine is an iodinated thymidine derivative with activity against HSV. Use of idoxuridine has been limited to topical application, since systemic administration is associated with significant myelosuppression. Idoxuridine (in topical 1% solution and 0.5% ointment formulations) has been used successfully for treatment of HSV keratitis, but has largely been replaced by topical trifluridine and aciclovir for this indication. Topical application of 15% idoxuridine in dimethyl sulfoxide was shown to shorten the course of herpes labialis in a placebo-controlled trial. If idoxuridine is the oldest antiviral, what is the newest? One candidate is lufotrelvir1, a compound disclosed in 2020 by researchers at multiple laboratories of Pfizer Worldwide Research and Development and other institutions. Lufotrelvir is a potential treatment for COVID-19, although, unlike some others, it must be administered intravenously. This month, Robert A. Singer and co-workers at Pfizer (Groton, CT) reported an improved synthesis of the relatively unstable lufotrelvir.

Concentrations of Idoxuridine in Serum, Urine, and Cerebrospinal Fluid of Patients

A reproducible microbiologic assay of microgram quantities of idoxuridine (IDU) in serum, urine, or cerebrospinal fluid is presented. The antiviral assay is not interfered with by type-specific antibody or interferon. During slow intravenous infusions of idox-uridine (4 mg/min) in patients with suspected diagnoses of Herpesvirus hominis encephalitis, the rate of inactivation and/or removal of drug exceeded its administration. Minimal inhibitory concentrations of IDU for fresh isolates of Herpesvirus hominis (type 1 or 2) were determined. Type 1 herpesviruses' microplaques in baby hamster kidney cell (BHK 21) tissue cultures were sensitive to 2.5-10 μg/0.4 ml. Type 2 macroplaques required 25-50 μg/0.4 ml. This latter characteristic may be an additional biologic marker which may be useful in suggesting type-specificity of herpesvirus isolates.[1]

During several rapid infusions of idoxuridine (50 mg/min) significant quantities of the drug were found in serum, urine, and cerebrospinal fluid. Idoxuridine is not significantly bound to serum proteins and is not deiodinated in fresh serum or urine in vitro to inactive products (iodouracil, uracil, iodide). It is rapidly excreted into the urine. Inactivation of IDU occurs in tissues. This antiviral assay of IDU in body fluids should be applicable to other viruses and potential antiviral agents.

Ineffectiveness of topical idoxuridine in dimethyl sulfoxide

The efficacy and toxicity of topical applications of 30% idoxuridine in dimethyl sulfoxide, dimethyl sulfoxide alone, or saline in 96 recurrent and 39 first episodes of genital herpes simplex virus (HSV) infection were compared. Drug was applied to lesions four times daily for seven days. In recurrent episodes, the duration of viral shedding after beginning idoxuridine in dimethyl sulfoxide use was significantly shorter (0.6 days) than with dimethyl sulfoxide (1.4 days) or saline (2.0 days) (P less than .05). In primary episodes, viral shedding lasted 2.6 days with idoxuridine in dimethyl sulfoxide and 8.4 days with dimethyl sulfoxide or saline. Furthermore, Idoxuridine in dimethyl sulfoxide had no effect in recurrent or primary HSV on duration of symptoms, new lesion formation, healing time, or risk of subsequent recurrence. Complications in patients given idoxuridine in dimethyl sulfoxide included local burning, generalized contact dermatitis, and vulvar carcinoma in situ. Thirty percent idoxuridine in dimethyl sulfoxide has no effect on clinical manifestations of genital HSV infection and may be hazardous.[2]

As a result, idoxuridine is able to replace thymidine in the enzymatic step of viral replication or "growth". The consequent production of faulty DNA results in a pseudostructure which cannot infect or destroy tissue. In short, by pre-empting a vital building block in the genetic material of the Herpes simplex virus, Herplex-D topical solution destroys the infective and destructive capacity of the viral material. The virus infected cell may only be attacked during the period of active synthesis of DNA. This occurs early in the development of the Herpes simplex lesion, but at different times in different cells. Therefore, ideally, the affected area should remain saturated with the antiviral agent.

References

[1]Lerner AM, Bailey EJ. Concentrations of idoxuridine in serum, urine, and cerebrospinal fluid of patients with suspected diagnoses of Herpesvirus hominis encephalitis. J Clin Invest. 1972 Jan;51(1):45-9. doi: 10.1172/JCI106795. PMID: 4331799; PMCID: PMC332927.

[2]Silvestri, D L et al. “Ineffectiveness of topical idoxuridine in dimethyl sulfoxide for therapy for genital herpes.” JAMA vol. 248,8 (1982): 953-9.