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Zovirax

Aciclovir (INN) or acyclovir (USAN), marketed as Zovirax®, is one of the main antiviral drugs. Its discovery has been seen as the start of a new era in antiviral therapy, as it is extremely selective and low in cytotoxicity. However, it has a very narrow spectrum, only effective against certain viruses such as HSV-1, HSV-2, and VZV, with limited effectiveness against active EBV, and has hardly any effect against human cytomegalovirus (CMV). It is about 10 times more potent against HSV than VZV. It does not eradicate latent herpes, and does not work very well against genital herpes in women. more...

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Aciclovir is rather different from other nucleoside analogues, for it contains only a partial nucleoside structure as the sugar ring is replaced by an open-chain structure.

Mode of action

Aciclovir is converted into monophosphate form only 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, aciclo-GTP, by cellular kinases. Aciclo-GTP is a very potent inhibitor of viral DNA polymerase; it has approximately 100 times higher affinity to viral than cellular polymerase. Its monophosphate form also incorporates into the viral DNA, resulting in chain termination. It has also been shown that the viral enzymes cannot remove acyclo-GMP 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.

Pharmacokinetics

Aciclovir suffers from low water solubility, and also from poor oral absorption, which is only 20%. Orally administered the peak plasma concentration will be reached in 1-2 hours. If large doses are required, aciclovir must be administered intravenously. Aciclovir has a high distribution rate, only 30 % is protein-bound in plasma. The half-life of aciclovir is approximately 3 hours. Aciclovir can also be given topically for treatment of herpes infections of mucous membrane and skin, such as genital herpes or recurrent herpes labialis (cold sore). Prophylactic administration is possible, and is often used for patients who are under immunosuppressant drugs or radiotherapy or for those who are suffering from recurrent genital infection herpes simplex.

Metabolism

The excretion of aciclovir takes place via the renal system, partly by glomerular filtration and partly by tubular secretion. Renal problems have been reported when given in large, fast doses intravenously, due to the crystallisation of aciclovir in the kidneys.

Side effects

Since aciclovir can be incorporated also into the cellular DNA, it is a chromosome mutagen, therefore, its use should be avoided during pregnancy. However it has not been shown to cause any teratogenic nor carcinogenic effects. The acute toxicity (LD₅₀) of aciclovir when given orally is greater than 1 g/kg, due to the low absorption rate from the gastrointestinal tract. Single cases have been reported, where extremely high (up to 80mg/kg) doses have been accidentally given intravenously without causing any side effects. The most common adverse effects are local irritation at the site of injection, headache when given orally, and a stinging and burning sensation when administered topically. The resistance towards aciclovir evolves rather rapidly, although this has not much hindered its clinical use. Resistant forms are most likely viruses that have a mutation in their thymidine kinase or DNA polymerase.

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Antiviral agents for pregnant women with genital herpes
From American Family Physician, 11/1/05 by Christopher Wenner

Clinical Question

Do antiviral medications prevent perinatal transmission of genital herpes to neonates?

Evidence-Based Answer

There is no evidence that the use of antiviral agents in women who are pregnant and have a history of genital herpes prevents perinatal transmission of herpes simplex virus (HSV) to neonates. [Strength of recommendation: A, based on multiple systematic reviews]

However, treatment with antivirals during the last month of pregnancy does reduce the rate of HSV outbreaks in pregnant women and the resultant need for cesarean delivery. [Strength of recommendation: A, based on multiple systematic reviews]

Evidence Summary

Neonatal herpes infection is the major consequence of maternal HSV. Fortunately, the transmission rate is quite low (less than 1 percent) for nonprimary HSV outbreaks. This poses a problem in assessing the effectiveness of antivirals for preventing this serious illness, because even a large meta-analysis is underpowered in addressing this issue.

One systematic review and one meta-analysis reviewed a total of five randomized controlled trials. Both reviews were of good quality. The trials involved pregnant women with recurrent and first-episode HSV infections. In each study, women were randomized to either acyclovir (Zovirax) or placebo for HSV prophylaxis beginning at 36 weeks' gestation. The dosages of acyclovir ranged from 800 to 1,200 mg per day. Acyclovir was the only antiviral agent evaluated in either study.

The aggregate data involved nearly 800 patients. There were no reported cases of neonatal HSV infection in either the treatment or placebo groups. There was good evidence that prophylaxis with antiviral agents during the last month of pregnancy was effective in reducing the rate of HSV outbreaks during the perinatal period in mothers with HSV infections (15 of 424 in the acyclovir group versus 58 of 375 in the placebo group had HSV outbreaks during the perinatal period, absolute risk reduction [ARR] = 11%, number needed to treat [NNT] = 9). Presumably because of the significant reduction in HSV recurrences with antiviral prophylaxis, the total cesarean delivery rate was significantly lower in the treatment group (17 versus 26 percent, ARR = 9%, NNT = 11) as well as the rate of cesarean delivery for HSV recurrence (4 versus 15 percent, ARR = 11%, NNT = 9). Treatment also eliminated the risk of laboratory-detected HSV infection at delivery (0 versus 5 percent, ARR = 5%, NNT = 20).

Recommendations from Others

The 2001 National Guideline for the Management of Genital Herpes, published by the Association for Genitourinary Medicine and the Medical Society for the Study of Venereal Disease, recommends the use of continuous acyclovir during the last month of pregnancy as a treatment option in women with recurrent genital herpes. (4) The American College of Obstetricians and Gynecologists (ACOG) recommends that women with a first episode of HSV during any stage of pregnancy should be treated with a seven- to 14-day course of an antiviral agent. ACOG also notes that for women at risk of recurrent HSV, initiation gestation. The of antiviral therapy during the last month of pregnancy may be warranted.

Clinical Commentary

With the evidence that antiviral treatment reduces the rates of maternal HSV outbreaks in the perinatal period and subsequent cesarean deliveries, one could argue that maternal morbidity and costs are decreased with treatment. A cheap, safe medicine (acyclovir) and a small NNT of 93 add credence to this argument. Despite the lack of data regarding the outcome of neonatal HSV infection, the sample size required is so large that such a study may never be performed. Thus, acyclovir use for the prevention of perinatal HSV in the final month of pregnancy appears to be a reasonable treatment option

REFERENCES

(1.) Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR Recomm Rep 2002;51:1-78.

(2.) Jungmann E. Genital herpes. Clin Evid 2004;12:2212-27. Accessed online August 19, 2005, at: http://www.clinicalevidence.com/ceweb/conditions/seh/1603/1603.jsp.

(3.) Sheffield JS, Hollier LM, Hill JB, Stuart GS, Wendel GD. Acyclovir prophylaxis to prevent herpes simplex virus recurrence at delivery: a systematic review. Obstet Gynecol 2003;102:1396-403.

(4.) Clinical Effectiveness Group (Association for Genitourinary Medicine and the Medical Society for the Study of Venereal Disease). 2001 National guideline for the management of genital herpes. Accessed online August 19, 2005, at: http://www.bashh.org/guidelines/2002/hsv_0601.pdf.

(5.) ACOG Practice Bulletin. Management of herpes in pregnancy. Number 8, October 1999. Clinical management guidelines for obstetrician-gynecologists. Obstet Gynecol 1999;94:1-10.

CHRISTOPHER WENNER, M.D. St. Cloud Hospital/Mayo Family Medicine Residency Program St. Cloud, Minnesota

JOAN NASHELSKY, M.L.S. Managing Editor and Librarian Coordinator Family Physicians Inquiries Network Iowa City, Iowa

Author disclosure: Nothing to disclose.

Address correspondence by e-mail to Christopher Wenner, M.D., wennerc@centracare.com. Reprints are not available from the authors.

Clinical Inquiries provides answers to questions submitted by practicing family physicians to the Family Physicians Inquiries Network (FPIN). Members of the network select questions based on their relevance to family medicine. Answers are drawn from an approved set of evidence-based resources and undergo peer review. The strength of recommendations and the level of evidence for individual studies are rated using criteria developed by the Evidence-Based Medicine Working Group (http:// www.cebm.net/levels_of_evidence.asp).

This series of Clinical Inquiries is coordinated for American Family Physician by John Epling, M.D., State University of New York Upstate Medical University, Syracuse, N.Y. The complete database of evidence-based questions and answers is copyrighted by FPIN. If you are interested in submitting questions to be answered or writing answers for this series, go to http://www. fpin.org or contact questions@fpin.org.

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