Aciclovir chemical structure
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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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New concepts in Bell's palsy improve treatment options
From American Family Physician, 7/1/05 by Anne D. Walling

Bell's palsy affects about one in 60 persons and has an annual incidence of around 20 per 100,000 persons. Overall, the condition is most common in persons 15 to 45 years of age, but the incidence is particularly high in pregnant women (45 per 100,000). Holland and Weiner outlined recent developments concerning the management of Bell's palsy.

Although still somewhat controversial, evidence is accumulating that reactivated herpes viruses (simplex type 1 or zoster) in cranial nerve ganglia are the most common cause of Bell's palsy. Conditions caused by the herpes zoster virus may be more severe than those caused by herpes simplex virus type 1.

Patients usually are alarmed by the sudden onset of Bell's palsy symptoms, which include facial weakness accompanied by change in taste sensation, hyperacusis, and decreased lacrimation. Some patients report ear pain or fullness before the paralysis. Severe pain is more typical of herpes zoster infections. Examination of a patient with Bell's palsy shows impaired facial and platysma muscles causing drooping of the mouth and brow plus difficulty closing the eye or mouth. The patient should be examined for evidence of other causes of lower facial weakness such as intracranial or parotid lesions or Lyme disease. Laboratory tests are not helpful in diagnosis except to exclude other potential causes of facial weakness.

Approximately 75 percent of patients recover fully from Bell's palsy, and 10 percent have minor sequelae. About one sixth of patients have residual moderate to severe weakness, contracture, spasm, or synkinesis. In patients who do not receive treatment, most improvement occurs within three weeks. Additional improvement is delayed for the four to six months required for nerve regeneration. Although prognosis cannot be predicted accurately, factors associated with poor outcome have been identified in the accompanying table.

The goals of treatment are to accelerate recovery and prevent or minimize complications. Patients may require considerable reassurance and support during this illness. The eye should be protected from drying by hourly use of lubricating drops while awake and eye ointment at night. Massage, facial exercises, and biofeedback can contribute to improvement but have not been studied extensively. Steroids have been shown to increase the proportion of patients with good outcome by 17 percent if used within seven days of symptom onset. Antiviral agents, such as acyclovir (Zovirax), are increasingly recommended in combination with steroids because of the accumulating evidence of a viral etiology of Bell's palsy. Because acyclovir has low bioavailability, studies are focusing on valacyclovir (Valtrex) and famciclovir (Famvir). One prospective controlled study showed enhanced recovery when valacyclovir was combined with prednisone. The effect was particularly noticeable in older patients. Ideally, patients should begin treatment within 72 hours of symptom onset. Surgical decompression is reserved for rare cases because of danger of adverse effects.

The authors conclude that patients with Bell's palsy should begin treatment immediately and be referred to a subspecialist. Patients with significant sequelae should be referred for multidisciplinary management that could include injections of botulinum toxin, facial reanimation, and cosmetic surgery.

Holland NJ, Weiner GM. Recent developments in Bell's palsy. BMJ September 4, 2004;329:553-7.

COPYRIGHT 2005 American Academy of Family Physicians
COPYRIGHT 2005 Gale Group

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