Cidofovir

Cidofovir, brand name Vistide, is a topical or injectable antiviral medication primarily used as a treatment for cytomegalovirus (CMV) retinitis (an infection of the retina of the eye) in people with AIDS.<ref name = MSR/><ref name =TGA/>

Cidofovir was approved for medical use in 1996.<ref>Template:Cite book</ref>

Medical use

DNA virus

Its only indication that has received regulatory approval worldwide is cytomegalovirus retinitis.<ref name = MSR/><ref name = TGA/> Cidofovir has also shown efficacy in the treatment of aciclovir-resistant HSV infections.<ref>Template:Cite journal</ref> Cidofovir has also been investigated as a treatment for progressive multifocal leukoencephalopathy with successful case reports of its use.<ref name="pmid11408993">Template:Cite journalTemplate:Dead link</ref> Despite this, the drug failed to demonstrate any efficacy in controlled studies.<ref>Template:Cite journal</ref> Cidofovir might have anti-smallpox efficacy and might be used on a limited basis in the event of a bioterror incident involving smallpox cases.<ref name="pmid12076747">Template:Cite journal</ref> Brincidofovir, a cidofovir derivative with much higher activity against smallpox that can be taken orally has been developed.<ref>Template:Cite journal</ref> It has inhibitory effects on varicella-zoster virus replication in vitro although no clinical trials have been done to date, likely due to the abundance of safer alternatives such as aciclovir.<ref>Template:Cite journal</ref> Cidofovir shows anti-BK virus activity in a subgroup of transplant recipients.<ref name="pmid16499584">Template:Cite journal</ref> Cidofovir is being investigated as a complementary intralesional therapy against papillomatosis caused by HPV.<ref name="pmid18458927">Template:Cite journal</ref><ref name="pmid18197029">Template:Cite journal</ref>

It first received FDA approval on 26 June 1996,<ref name = drugs.com>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> TGA approval on 30 April 1998<ref name = TGA/> and EMA approval on 23 April 1997.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

It has been used topically to treat warts.<ref>Template:Cite journal</ref>

Other

It has been suggested as an antitumour agent, due to its suppression of FGF2.<ref name="pmid17158200">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Administration

Cidofovir is only available as an intravenous formulation. Cidofovir is to be administered with probenecid which decreases side effects to the kidney.<ref name="gilead.com">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Probenecid mitigates nephrotoxicity by inhibiting organic anion transport of the proximal tubule epithelial cells of the kidney.<ref name="pmid9742650">Template:Cite journal</ref> In addition, hydration must be administered to patients receiving cidofovir. 1 liter of normal saline is recommended in conjunction with each dose of cidofovir.<ref name="gilead.com"/>

Side effects

The major dose-limiting side effect of cidofovir is nephrotoxicity (i.e., kidney damage).<ref name="AMH">Template:Cite book</ref> Other common side effects (occurring in >1% of people treated with the drug) include:<ref name = MSR>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name = AMH/> Template:Div col

• Nausea
• Vomiting
• Neutropenia
• Hair loss
• Weakness
• Headache
• Chills
• Decreased intraocular pressure
• Uveitis
• Iritis

Template:Div col end Whereas uncommon side effects include: anaemia and elevated liver enzymes and rare side effects include: tachycardia and Fanconi syndrome.<ref name = AMH/> Probenecid (a uricosuric drug) and intravenous saline should always be administered with each cidofovir infusion to prevent this nephrotoxicity.<ref name="vistide">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Contraindications

Hypersensitivity to cidofovir or probenecid (as probenecid needs to be given concurrently to avoid nephrotoxicity).<ref name = MSR/>

Interactions

It is known to interact with nephrotoxic agents (e.g. amphotericin B, foscarnet, IV aminoglycosides, IV pentamide, vancomycin, tacrolimus, non-steroid anti-inflammatory drugs, etc.) to increase their nephrotoxic potential.<ref name = MSR/><ref name = TGA>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> As it must be given concurrently with probenecid it is advised that drugs that are known to interact with probenecid (e.g. drugs that probenecid interferes with the renal tubular secretion of, such as paracetamol, aciclovir, aminosalicylic acid, etc.) are also withheld.<ref name = TGA/>

Mechanism of action

Its active metabolite, cidofovir diphosphate, inhibits viral replication by selectively inhibiting viral DNA polymerases.<ref name =TGA/> It also inhibits human polymerases, but this action is 8–600 times weaker than its actions on viral DNA polymerases.<ref name =TGA/> It also incorporates itself into viral DNA, hence inhibiting viral DNA synthesis during reproduction.<ref name = TGA/>

It possesses in vitro activity against the following viruses:<ref>Template:Cite journal</ref>

• Human herpesviruses
• Adenoviruses
• Human poxviruses (including the smallpox virus)
• Human papillomavirus

History

Cidofovir was discovered at the Institute of Organic Chemistry and Biochemistry, Prague, by Antonín Holý, and developed by Gilead Sciences<ref name="titlePress Releases: Gilead">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and is marketed with the brand name Vistide by Gilead in the US, and by Pfizer elsewhere.

Synthesis

Cidofovir can be synthesized from a pyrimidone derivative and a protected derivative of glycidol.<ref>Template:Cite journal</ref>

File:Cidofovir syn.png

See also

• Brincidofovir, a prodrug of cidofovir