Idoxuridine (C9H11IN2O5; 5-iodo-2u-deoxyuridine; IUdR; IDU) is an analog of the pyrimidine nucleoside thymidine. It was synthesized in 1959 by William Prusoff as a possible anti-tumor agent (Prusoff, 1959) and was later shown to inhibit replication of herpes simplex and vaccinia viruses in cell culture. Subsequently, clinical trials by Herbert Kaufman documented idoxuridine’s beneficial effects in patients with herpes simplex virus (HSV) keratitis, and this remains idoxuridine’s only significant clinical indication. 

Idoxuridine is of considerable historical interest as it was the first antiviral drug to be widely used clinically, for topical treatment of herpes keratitis. For a few years before 1975, it was given systemically as treatment for herpes simplex encephalitis, and numerous anecdotes and case series suggested that it shortened recovery and reduced long-term disability from this disease. However, when a placebo-controlled clinical trial was finally conducted intravenous idoxuridine was shown to have no salutary effect on the course or outcome of herpes simplex encephalitis, despite frequent and severe adverse reactions in other organ systems. 

Idoxuridine is marketed under a number of trade names including Dendrids, Herplexs, Herpids, Stoxils, Idoxenes, and Virudoxs .  Idoxuridine is available as an ophthalmic solution that contains not less than 0.09% and not more than 0.11% idoxuridine, or as an ophthalmic ointment that contains not less than 0.45% and not more than 0.55% idoxuridine.

MECHANISM OF DRUG ACTION 

The chemical structure of idoxuridine, a nucleoside analog, closely approximates that of thymidine, one of the four nucleosides that make up DNA (the genetic material of herpesviruses and poxviruses). Like other nucleoside analogs, idoxuridine is a prodrug which must be triphosphorylated before it is active. Idoxuridine, like aciclovir and penciclovir , is monophosphorylated in herpesvirus-infected cells by a virus-specified thymidine kinase. This is also the case with vaccinia virus. The drug is subsequently diand triphosphorylated by cellular enzymes. Idoxuridine triphosphate inhibits the synthesis of DNA in normal human tissue cells and in DNA viruses. Idoxuridine triphosphate competes with thymidine, an essential constituent of DNA, and it inhibits thymidylic phosphorylase and the virus-coded DNA polymerases required for the incorporation of thymidine into viral DNA. Substitution of 0.1– 1% of the thymidine residues in the DNA of varicella-zoster virus by idoxuridine inhibits the replication of the virus. Idoxuridine is incorporated into both viral and mammalian DNA. The antiviral activity of idoxuridine is reversed by thymidine.

PHARMACOKINETICS 

Idoxuridine has only limited penetration of the cornea, owing to poor permeability of the polar drug across the lipoidal epithelial layer of the cornea. Levels of idoxuridine in the stratum corneum of guinea-pig skin peak 1–3 hours after topical application and then gradually decline over the next 3–24 hours. When glycyrrhizin gel is used as a carrier, the idoxuridine preparation penetrates the skin more effectively than the commercial ointment.

TOXICITY

Most first-generation antiviral nucleosides (including idoxuridine and trifluorothymidine) were poorly selective for virus-infected cells and proved to be too toxic for systemic administration; they are now used only for topical application. Instillation in the eye may occasionally cause an allergic reaction or inflammation with resultant pain and pruritus in the eye or eyelids. If idoxuridine is instilled more frequently than recommended, small defects may appear on the cornea, in which case the drug should be discontinued. Follicular conjunctivitis and punctate keratopathy have been reported. Boric acid should not be used in the eye with idoxuridine because interactions between boric acid and inert ingredients present in some formulations of idoxuridine result in precipitation. Idoxuridine therapy is not recommended in pregnancy as fetal malformations and chromosomal aberrations have been reported in rabbits and mice treated with the drug (admittedly at far higher systemic exposure than would result from topical ophthalmic therapy in humans). Side-effects from mucosal therapy are reportedly minimal.