Идоксуридин

Химические свойства

Crystalline Solid

Использование

Idoxuridine is an antiviral agent effective against herpes-simplex infections; in ophthalmie eyedrops, ointments, and solutions.

Показания

Idoxuridine (Herplex) is a water-soluble iodinated derivative of deoxyuridine that inhibits several DNA viruses including HSV, VZV, vaccinia, and polyoma virus. The triphosphorylated metabolite of idoxuridine inhibits both viral and cellular DNA synthesis and is also incorporated into DNA. Such modified DNA is susceptible to strand breakage and causes aberrant viral protein synthesis. Because of its significant host cytotoxicity, idoxuridine cannot be used to treat systemic viral infections. The development of resistance to this drug is common.

Определение

ChEBI: A pyrimidine 2'-deoxyribonucleoside compound having 5-iodouracil as the nucleobase; used as an antiviral agent.

Фармацевтические приложения

A halogenated pyrimidine analog originally synthesized as an anticancer agent. Formulated in dimethylsulfoxide for topical application and as a solution for ophthalmic use.
Activity is largely limited to DNA viruses, primarily HSV-1, HSV-2 and VZV. HSV-1 plaque formation in BHK 21 cells is sensitive to 6.25–25 mg/L; type 2 microplaques required 62.5–125 mg/L. RNA viruses are not affected, with the exception of oncogenic RNA viruses such as Rous sarcoma virus. Drug resistance is easily generated in vitro, and may be an obstacle to treatment. However, there is little or no crossresistance with newer nucleoside analogs.
It is poorly soluble in water, and aqueous solutions are ineffective against infections other than those localized to the eye. In animals, therapeutic levels are achieved in the cornea within 30 min of ophthalmic application and persist for 4 h. Penetration is otherwise poor, with only the biologically inactive dehalogenated metabolite uracil entering the eye.
The drug is too toxic for systemic administration. Contact dermatitis, punctate epithelial keratopathy, follicular conjunctivitis, ptosis, stenosis and occlusion of the puncta and keratinization of the lid margins occur in up to 14% of those receiving ophthalmic preparations.
It is used in herpes keratitis, but has largely been superseded by trifluridine or aciclovir.

Механизм действия

Idoxuridine is a nucleoside containing a halogenated pyrimidine and is an analogue of thymidine. It acts as an antiviral agent against DNA viruses by interfering with their replication based on the similarity of structure between thymidine and idoxuridine. Idoxuridine is first phosphorylated by the host cell virusencoded enzyme thymidine kinase to an active triphosphate form. The phosphorylated drug inhibits cellular DNA polymerase to a lesser extent than HSV DNA polymerase, which is necessary for the synthesis of viral DNA. The triphosphate form of the drug is then incorporated during viral nucleic acid synthesis by a false pairing system that replaces thymidine. When transcription occurs, faulty viral proteins are formed, resulting in defective viral particles.

Клиническое использование

The only FDA-approved use of idoxuridine is in the treatment of herpes simplex infections of the eyelid, conjunctiva conjunctiva, and cornea. It is most effective against surface infections because it has little ability to penetrate the tissues of the eye. intravenous idoxuridine was designated an orphan drug for the treatment of soft tissue sarcoma.

Побочные эффекты

Idoxuridine may cause local irritation, mild edema, itching, and photophobia. Corneal clouding and small punctate defects in the corneal epithelium have been reported. Allergic reactions are rare.

Профиль безопасности

Moderately toxic by intraperitoneal route. Experimental teratogenic and reproductive effects. Questionable carcinogen with experimental carcinogenic data. Human mutation data reported. When heated to decomposition it emits very toxic fumes of Iand NOx.

Метаболизм

Idoxuridine is metabolized rapidly in the body to iodouracil, uracil, and iodide. Metabolites are excreted in the urine.