Ganciclovir
[CAS# 82410-32-0]

Identification

• Classification: API >> Synthetic anti-infective drugs >> Antiviral drugs
• Name: Ganciclovir
• Synonyms: 2-Amino-1,9-dihydro-9-((2-hydroxy-1-(hydroxymethyl)ethoxy)methyl)-6H-purin-6-one; 9-((2-Hydroxy-1-(hydroxymethyl)ethoxy)-methyl)guanine; 9-(1,3-Dihydroxy-2-propoxymethyl)guanine; 2'-NDG; 2'-Nor-2'-deoxyguanosine
• Molecular Formula: C₉H₁₃N₅O₄
• Molecular Weight: 255.23
• CAS Registry Number: 82410-32-0
• EC Number: 627-054-3
• SMILES: C1=NC2=C(N1COC(CO)CO)N=C(NC2=O)N

Properties

• Solubility: 50 mg/mL (DMSO), ,1 mg/mL (water) (Expl.)
• Density: 1.8±0.1 g/cm³, Calc.^*
• Index of Refraction: 1.761, Calc.^*

Safety Data

• Hazard Symbols: GHS08 Danger
• Risk Statements: H360
• Safety Statements: P203-P280-P318-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Reproductive toxicity	Repr.	1B	H360
Reproductive toxicity	Lact.	-	H362
Carcinogenicity	Carc.	2	H351
Germ cell mutagenicity	Muta.	1B	H340
Reproductive toxicity	Repr.	2	H361
Specific target organ toxicity - repeated exposure	STOT RE	2	H373

Discovery and Applications

Ganciclovir is an antiviral medication that is primarily used to treat infections caused by cytomegalovirus (CMV), a member of the herpesvirus family. It is particularly effective in preventing and treating CMV infections in immunocompromised individuals, such as those with HIV/AIDS, transplant recipients, or patients undergoing chemotherapy. Ganciclovir is also used to treat CMV retinitis, a serious eye infection that can occur in people with advanced HIV/AIDS.

The discovery of ganciclovir dates back to the 1980s, when researchers were investigating ways to combat viral infections caused by CMV, a pathogen that is commonly encountered in immunocompromised patients. Ganciclovir is a synthetic acyclic guanine derivative, structurally related to acyclovir, another antiviral drug. Both drugs share similar mechanisms of action, but ganciclovir is more potent against CMV due to its ability to specifically inhibit CMV DNA polymerase, an enzyme critical for viral replication.

Ganciclovir works by incorporating itself into the viral DNA during replication. Once incorporated, it acts as a chain terminator, preventing the elongation of the DNA strand and halting further viral replication. It is a prodrug, meaning that it needs to be activated within the infected cell to exert its antiviral effect. This activation is carried out by the viral enzyme CMV thymidine kinase, which converts ganciclovir into its active form, ganciclovir triphosphate. Ganciclovir triphosphate then competes with the natural nucleotide guanosine and gets incorporated into the growing DNA chain, disrupting the replication process.

In clinical practice, ganciclovir is most commonly administered intravenously (IV) for the treatment of severe CMV infections, such as CMV retinitis in immunocompromised patients. It is also used as a preventive measure to reduce the risk of CMV reactivation in organ transplant recipients, especially those who are at high risk. Oral formulations of ganciclovir are available as well, though they are less commonly used because of their relatively poor bioavailability when compared to the IV form.

One of the major challenges with ganciclovir is its toxicity. The drug can cause a range of side effects, some of which can be severe. Common side effects include hematological effects such as neutropenia (low white blood cell count), thrombocytopenia (low platelet count), and anemia. These side effects occur because ganciclovir inhibits the replication of not only the viral DNA but also the DNA in human cells, including those of the bone marrow. For this reason, patients receiving ganciclovir are closely monitored for changes in blood counts.

Other potential side effects include gastrointestinal disturbances like nausea and vomiting, liver enzyme abnormalities, and renal dysfunction. Ganciclovir can also cause central nervous system effects, such as headache, confusion, and seizures, although these are less common. Because of its potential for causing significant side effects, ganciclovir is usually reserved for severe cases of CMV infection or for patients who are at high risk of such infections.

Due to its toxicity, ganciclovir is generally only prescribed for patients who are severely immunocompromised or those who have life-threatening CMV infections. It is also important to note that ganciclovir requires dose adjustments in patients with renal impairment, as the drug is primarily eliminated by the kidneys. The risk of toxicity is increased in patients with pre-existing kidney dysfunction, so caution is necessary when administering the drug in such individuals.

Resistance to ganciclovir can develop in patients who have received long-term or repeated treatment, particularly in those with HIV/AIDS. Resistance typically occurs due to mutations in the CMV gene encoding the viral DNA polymerase or the thymidine kinase enzyme. This can lead to treatment failure, making it essential to monitor patients for signs of drug resistance during prolonged therapy.

An alternative to ganciclovir in patients with CMV resistance or intolerance is valganciclovir, an oral prodrug of ganciclovir. Valganciclovir is converted to ganciclovir in the body and offers the advantage of oral administration, although it also has similar side effects and requires monitoring.

In addition to its use in treating CMV infections, ganciclovir has been investigated for its potential use against other herpesviruses, such as Epstein-Barr virus (EBV) and herpes simplex virus (HSV), although its use in these areas is less established. Researchers continue to explore the drug’s potential in the treatment of other viral infections, but its primary role remains in the management of CMV-related diseases.

In summary, ganciclovir is an important antiviral medication that is primarily used to treat and prevent CMV infections in immunocompromised patients. It works by inhibiting viral DNA replication, but its use is limited by potential side effects, especially hematological toxicity. As with any antiviral treatment, ganciclovir should be used under the guidance of a healthcare provider, and patients should be closely monitored for adverse effects during therapy.

References

1982. A new nucleoside analog, 9-[[2-hydroxy-1-(hydroxymethyl)ethoxyl]methyl]guanine, highly active in vitro against herpes simplex virus types 1 and 2. Antimicrobial Agents and Chemotherapy, 22(1).
DOI: 10.1128/aac.22.1.55

1998. The Novel Immunosuppressive Agent Mycophenolate Mofetil Markedly Potentiates the Antiherpesvirus Activities of Acyclovir, Ganciclovir, and Penciclovir In Vitro and In Vivo. Antimicrobial Agents and Chemotherapy, 42(2).
DOI: 10.1128/aac.42.2.216

2000. EFFICACY OF THE GANCICLOVIR IMPLANT IN THE SETTING OF SILICONE OIL VITREOUS SUBSTITUTE. Retina (Philadelphia, Pa.), 20(5).
DOI: 10.1097