GANCICLOVIR

Andi Cahyadi

Ganciclovir is a guanosine nucleoside analogue, homologue Acyclovir and the first antiviral drug effective in treating cytomegalovirus in humans. Ganciclovir inhibits not only herpes virus but also the transformation of lymphocytes by the Ebstein Barr Virus. (Crumpacker, 1996; Marshall and Koch, 2009)

Mechanisms and How to Work Ganciclovir

Ganciclovir in vivo transformed into Ganciclovir triphosphate which inhibits viral DNA polymerase, including Herpes Simplex Virus and CMV, by way of competitive inhibitors on deoksiguanosine triphosphate formation in viral DNA elongation. (Marshall and Koch, 2009) After removing pyrophosphate, Ganciclovir monophosphate binds to the end of the formation thereby inhibiting replication of DNA chains. (Crumpacker, 1996) Unlike acyclovir, Ganciclovir is not an absolute chain terminator so that the sub-genomic fragment of CMV remains synthesized in short segment. All antiviral drugs work because of its ability to inhibit CMV DNA synthesis and inhibits elongation in DNA replication. In the cells infected with herpes simplex virus, thymidine kinase phosphorylate the virus into a form Ganciclovir monophosphate and cellular enzymes further modify Ganciclovir Ganciclovir monophosphate to triphosphate which can inhibit viral DNA synthesis. (Crumpacker, 1996)

CMV does not have the enzyme thymidine kinase homologous and as an alternative is to phosphorylate UL97 gene product Ganciclovir. CMV UL97 kinase gene insertion into the vaccinia virus Ganciclovir incentives make recombinan virus susceptible to Ganciclovir. (Crumpacker, 1996)

Left half Ganciclovir triphosphate in CMV-infected cells was 16.5 hours compared to acyclovir triphosphate which is only 2.5 hours. In the circumstances molar base, Ganciclovir not as effective as acyclovir triphosphate as a DNA polymerase inhibitor, but the concentration of CMV in CMV-infected cells ten times greater than with acyclovir. Ganciclovir triposfat high levels and a long intracellular half-life makes Ganciclovir is considered to be superior compared with acyclovir in inhibiting replication of CMV. (Crumpacker, 1996; Marshall and Koch, 2009)

 Pharmacokinetic and Toxicity of Ganciclovir

Giving intravenous Ganciclovir 5 mg/kg in one hour produces the peak concentration in serum 8.3 g/ml at the end of infusion. Ganciclovir in the plasma half-life was 2.9 hours and the average clearance of 3.9 ml per kilogram per minute. Twelve hours after the infusion, serum concentrations of less than 0.5 ug/ml. Regimen from 7.5 to 10.0 mg Ganciclovir per kilogram of body weight divided in 2 doses per day will produce peak serum concentrations from 4.5 to 10 ug/ml. Ganciclovir had the blood brain barrier penetration to produce a concentration in cerebrospinal fluid 0.7 ug/ml when measured simultaneously in plasma levels of 2.2 ug/ml within 3.5 hours after administration of intravenous 2.5 mg/kg. After treatment with Ganciclovir 1000 mg orally 3 times per day, maximum and minimum concentration in plasma was 1.2 and 0.2 ug/ml. Ganciclovir oral bioavailability is between 6-9%. Serum concentration has been entered in the ED50 in most isolates of CMV (0.2 to 1.6 g/ml). (Crumpacker, 1996)

Ganciclovir causes granulositopenia, thrombocytopenia, azoospermia and increased serum creatinine. Patients with CMV retinitis treated with intravenous Ganciclovir 3 months, 40% will have granulositopenia (neutrophil count <1000 per cm3) and 15% had thrombocytopenia <50,000 cm3. Granulositopenia and thrombocytopenia did not look after Ganciclovir was stopped except for one patient who suffered irreversible neutropenia and Pseudomonas sepsis. Anemia may also appear on the long-term treatment. The incidence of thrombocytopenia and granulositopenia on oral administration is rare than intravenously. Granulositopenia can be prevented by giving recombinant granulocyte colony stimulating factor or granulocyte macrophage colony stimulating factor. Patients will have a lower granulositopenia episode. (Crumpacker, 1996)

Twenty percent of the 20 people who received bone marrow transplant will experience an increase in serum creatinine over 2.5 mg/dl (221 μmol per liter) after 120 days of intravenous Ganciclovir. Serum creatinine returned to normal after Ganciclovir was stopped. Ganciclovir is more dangerous when used in conjunction with a toxic drug in the bone marrow such as zidovudine. Eighty percent of the 40 people require a dose reduction because of hematological toxicity of Ganciclovir and zidovudine. (Crumpacker, 1996) azoospermia associated with the provision of Ganciclovir on animal studies due to a direct effect on sperm production constraints. Testicular endocrine function is not affected but the data on experimental animals showed suppression of fertility may occur. (Crumpacker, 1996)

Clinical Use Ganciclovir

Ganciclovir inhibits the growth of CMV from laboratory isolates and clinical isolates with plasma concentrations of 0.1 to 1.6 ug / ml. (Crumpacker, 1996) Ganciclovir is more active than acyclovir in inhibiting replication of CMV. In tissue culture, Ganciclovir has antiviral activity against viruses amazing Herpes Simplex type 1 and 2, Varicela Zoster virus, Ebstein-Barr Virus and Human Herpes Virus 6. (Crumpacker, 1996) Ganciclovir is less effective against human adeno virus, human papilloma virus, Influenza virus and other RNA viruses. (Crumpacker, 1996; Marshall and Koch, 2009)

Ganciclovir is a synthetic nucleotide analog guanosine acyclik, phosphorylated to triphosphate in the cell and acts as an inhibitor of viral DNA synthesis. In preliminary data, it is effective for treating symptomatic CMV. (Whitley et al, 1997) Phase II study, Ganciclovir showed improvement or stabilization of hearing 4 of 30 infants with congenital CMV infection are symptomatic after 6 months or more. (Whitley et al, 1997) During the treatment period, expenditure decreased quantitatively virus in urine, but after treatment, again as in earlier viremia before treatment. (Leung et al, 2003) phase III randomized study, Ganciclovir beneficial in children with severe congenital CMV infection. (Pass, 2002) central nervous system damage that has occurred can not be repaired but the damage can be prevented before they happen. Ganciclovir for the treatment of lost hearing in children with CMV asipmtomatik is rare. (Leung et al, 2003) Ganciclovir Side effects include bone marrow suppression and toxic to the gonads should be a lot of rethinking. (Numazaki and Chiba, 1997), but not enough data to decide termination of the use of Ganciclovir in the treatment of neonatal CMV hepatitis

 

REFERENCES

 Whitley R, Cloud G, Gruber W, Storch GA, Demmler GJ, Jacobs RF, et al. Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: Results of a phase II study. J Infect Dis. 1997; 175: 1080-1086.

Marshall BC, Koch WC. Antivirals for cytomegalovirus infection in neonates and infants: focus on pharmacokinetics, formulations, dosing, and adverse events. Paediatr Drugs. 2009;11(5):309-21.

Crumpacker, CS. Ganciclovir. New Engl J Med 1996;335:721–729.

Numazaki K, Chiba S. Current aspects of diagnosis and treatment of cytomegalovirus infection in infants. Clin Diagn Virol. 1997; 8: 169-181.

Leung AKC, Sauve RS, Davies D. Congenital Cytomegalus Infection. J Natl MedAssoc. 2003;95:213-218.)

Pass RF. Cytomegalovirus infection. Pediatr Rev 2002; 23:163-169.