Acycloguanosine used as a medicine

1. Indications of acycloguanosine

(1) Herpes simplex virus infection: used for oral genital herpes virus infection of primary and recurrent cases; recurrent oral this product used to prevent cases. Injection for people has immunodeficiency. Prevention and treatment of primary and recurrent mucocutaneous infection and recurrent cases; also used in the treatment of herpes simplex encephalitis.

(2) Herpes zoster: oral treatment for immunocompetent individuals with herpes and immunodeficiency mild case. Injection is just for the treatment of severe herpes patients with immunodeficiency.

(3) Treatment of immunodeficiency varicella.

(4) Local for early genital herpes infection and immunodeficiency caused by herpes simplex virus self limiting mucocutaneous herpes simplex initial treatment and relapse cases.

(5) Treatment of acute retinal necrosis with its sodium salt

2. Pharmacological mechanism of acycloguanosine

Acycloguanosine is a kind of disease resistant poison. It has inhibition on herpes simplex virus, varicella zoster virus, cytomegalovirus and so on in vitro. This good entering the herpes virus infected cells, and deoxynucleoside competition virus thymidine kinase or cell kinase, then through two ways to inhibit virus replication:

(1) Disturbance of virus DNA polymerase, suppression of viral replication.

(2) In the DNA polymerase function, combined with the growth of the DNA chain, DNA chain elongation caused by interruption.

Acycloguanosine has a special affinity for the virus, but to a mammalian host cell toxicity.

3. Adverse reactions

(1) The common adverse reactions

The injection site or phlebitis inflammation, skin itching or hives, have a fever, rash, headache, nausea, mild,Vomiting, diarrhea, urinary protein, blood urea nitrogen and serum creatinine values increased, abnormal liver function such as serum aminotransferase, lactate dehydrogenase, alkaline phosphatase, total bilirubin slightly higher.

(2) Uncommon adverse reactions

Acute renal insufficiency, white and red blood cells decreased, decreased hemoglobin, neutropenia, idiopathic thrombocytopenic purpura, cholesterol, triglyceride, hematuria, hypotension, Dohan, palpitations, difficulty breathing, chest tightness.

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Acycloguanosine，a kind of drug

Acycloguanosine is a guanosine analogue antiviral drug, marketed under trade names such as Cyclovir, Herpex, Acivir, Acivirax, Zovirax, Zoral, and Xovir. One of the most commonly used antiviral drugs, it is primarily used for the treatment of herpes simplex virus infections, as well as in the treatment of varicella zoster (chickenpox) and herpes zoster (shingles).

Acycloguanosine was seen as the start of a new era in antiviral therapy, as it is extremely selective and low in cytotoxicity. Nucleosides isolated from a Caribbean sponge, Cryptotethya crypta, were the basis for the synthesis of Acycloguanosine. It was discovered by Howard Schaffer following his work with Robert Vince, S. Bittner and S. Gurwara on the adenosine analog acycloadenosine which showed promising antiviral activity. Later, Schaffer joined Burroughs Wellcome and continued the development of Acycloguanosine with pharmacologist Gertrude B. Elion. Vince later went on to invent abacavir, an nRTI drug for HIV patients. Elion was awarded the 1988 Nobel Prize in Medicine, partly for the development of Acycloguanosine . Dr. Richard Whitley, a University of Alabama at Birmingham researcher and pioneer in antiviral therapy, was the first to successfully use the drug in humans.

Acycloguanosinediffers from previous nucleoside analogues in containing only a partial nucleoside structure: the sugar ring is replaced with an open-chain structure. It is selectively converted into acyclo-guanosine monophosphate (acyclo-GMP) by viral thymidine kinase, which is far more effective (3000 times) in phosphorylation than cellular thymidine kinase.

Subsequently, the monophosphate form is further phosphorylated into the active triphosphate form, acyclo-guanosine triphosphate (acyclo-GTP), by cellular kinases. Acyclo-GTP has approximately 100 times greater affinity for viral than cellular polymerase. As a substrate, acyclo-GTP is incorporated into viral DNA, resulting in premature chain termination. Although Acycloguanosine

resembles a nucleotide, it has no 3' end. Therefore, after its incorporation into a growing DNA strand, no further nucleotides can be added to this strand. It has also been shown that viral enzymes cannot remove acyclo-GTP from the chain, which results in inhibition of further activity of DNA polymerase. Acyclo-GTP is fairly rapidly metabolised within the cell, possibly by cellular phosphatases.

In sum, Acycloguanosine can be considered a prodrug: it is administered in an inactive (or less active) form and is metabolised into a more active species after administration.

Acycloguanosine is active against most species in the herpesvirus family. In descending order of activity:

•     Herpes simplex virus type I (HSV-1)

•     Herpes simplex virus type II (HSV-2)

•     Varicella zoster virus (VZV)

•     Epstein-Barr virus (EBV)

•     Cytomegalovirus (CMV) – least activity

Activity is predominantly against HSV, and to a lesser extent VZV. It is only of limited efficacy against EBV and CMV. It is inactive against latent viruses in nerve ganglia.

Resistance to Acycloguanosine is rare, but is more common in patients on chronic antiviral prophylaxis (transplant recipients, people with acquired immunodeficiency syndrome due to HIV infection). Mechanisms of resistance in HSV include deficient viral thymidine kinase; and mutations to viral thymidine kinase and/or DNA polymerase, altering substrate sensitivity. Acycloguanosine has also shown cross-resistance with valAcycloguanosine and famciclovir.

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