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 The HIV, human immunodeficiency virus (HIV) is a retrovirus that attacks the immune system. Without treatment, it can lead to a spectrum of conditions including acquired immunodeficiency syndrome (AIDS). It is a Preventive healthcare, pr ...

. Cidofovir was approved for medical use in 1996.

Medical use

DNA virus

Its only indication that has received regulatory approval worldwide is cytomegalovirus retinitis. Cidofovir has also shown efficacy in the treatment of aciclovir-resistant HSV infections. Cidofovir has also been investigated as a treatment for progressive multifocal leukoencephalopathy with successful case reports of its use. Despite this, the drug failed to demonstrate any efficacy in controlled studies. Cidofovir might have anti-

smallpox Smallpox was an infectious disease caused by Variola virus (often called Smallpox virus), which belongs to the genus '' Orthopoxvirus''. The last naturally occurring case was diagnosed in October 1977, and the World Health Organization (W ...

efficacy and might be used on a limited basis in the event of a bioterror incident involving smallpox cases.

Brincidofovir Brincidofovir, sold under the brand name Tembexa, is an antiviral drug used to treat smallpox. Brincidofovir is a prodrug of cidofovir. Conjugated to a lipid, the compound is designed to release cidofovir intracellularly, allowing for higher int ...

, a cidofovir derivative with much higher activity against smallpox that can be taken orally has been developed. 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. Cidofovir shows anti- BK virus activity in a subgroup of transplant recipients. Cidofovir is being investigated as a complementary intralesional therapy against papillomatosis caused by HPV. It first received FDA approval on 26 June 1996, TGA approval on 30 April 1998 and EMA approval on 23 April 1997. It has been used topically to treat warts.

Other

It has been suggested as an antitumour agent, due to its suppression of FGF2.

Administration

Cidofovir is only available as an intravenous formulation. Cidofovir is to be administered with probenecid which decreases side effects to the kidney. Probenecid mitigates nephrotoxicity by inhibiting organic anion transport of the proximal tubule epithelial cells of the kidney. In addition, hydration must be administered to patients receiving cidofovir. 1 liter of normal saline is recommended in conjunction with each dose of cidofovir.

Side effects

The major dose-limiting side effect of cidofovir is nephrotoxicity (i.e., kidney damage). Other common side effects (occurring in >1% of people treated with the drug) include: * Nausea * Vomiting * Neutropenia * Hair loss * Weakness * Headache * Chills * Decreased intraocular pressure * Uveitis * Iritis Whereas uncommon side effects include: anaemia and elevated liver enzymes and rare side effects include:

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...

and Fanconi syndrome. Probenecid (a uricosuric drug) and intravenous saline should always be administered with each cidofovir infusion to prevent this nephrotoxicity.

Contraindications

Hypersensitivity to cidofovir or probenecid (as probenecid needs to be given concurrently to avoid nephrotoxicity).

Interactions

It is known to interact with nephrotoxic agents (e.g.

amphotericin B Amphotericin B is an antifungal medication used for serious fungal infections and leishmaniasis. The fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, and cryptococ ...

, foscarnet, IV

aminoglycosides Aminoglycoside is a medicinal chemistry, medicinal and bacteriology, bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside ...

, IV pentamide,

vancomycin Vancomycin is a glycopeptide antibiotic medication used to treat certain bacterial infections. It is administered intravenously ( injection into a vein) to treat complicated skin infections, bloodstream infections, endocarditis, bone an ...

tacrolimus Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After Allotransplantation, allogenic organ transplant, the risk of organ Transplant rejection, rejection is moderate. To lower the risk of organ rejectio ...

, non-steroid anti-inflammatory drugs, etc.) to increase their nephrotoxic potential. 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.

Mechanism of action

Its active metabolite, cidofovir diphosphate, inhibits viral replication by selectively inhibiting viral

DNA polymerases A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create t ...

. It also inhibits human polymerases, but this action is 8–600 times weaker than its actions on viral DNA polymerases. It also incorporates itself into viral DNA, hence inhibiting viral DNA synthesis during reproduction. It possesses ''in vitro'' activity against the following viruses: * Human herpesviruses *

Adenoviruses Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from the ...

* Human

poxviruses ''Poxviridae'' is a family of double-stranded DNA viruses. Vertebrates and arthropods serve as natural hosts. The family contains 22 genera that are assigned to two subfamilies: ''Chordopoxvirinae'' and ''Entomopoxvirinae''. ''Entomopoxvirinae'' ...

(including the

virus) *

Human papillomavirus Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and r ...

History

Cidofovir was discovered at the Institute of Organic Chemistry and Biochemistry, Prague, by Antonín Holý, and developed by

Gilead Sciences Gilead Sciences, Inc. () is an American biopharmaceutical company headquartered in Foster City, California, that focuses on researching and developing antiviral drugs used in the treatment of HIV/AIDS, hepatitis B, hepatitis C, influenza, and CO ...

and is marketed with the brand name Vistide by Gilead in the US, and by

Pfizer Pfizer Inc. ( ) is an American Multinational corporation, multinational Pharmaceutical industry, pharmaceutical and biotechnology corporation headquartered at The Spiral (New York City), The Spiral in Manhattan, New York City. Founded in 184 ...

elsewhere.

Synthesis

Cidofovir can be synthesized from a pyrimidone

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

and a protected derivative of glycidol. : Cidofovir syn

References

{{Antivirals Gilead Sciences Anti-herpes virus drugs Pyrimidones Amines Ethers Phosphonic acids Primary alcohols