Valaciclovir, also spelled valacyclovir, is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster(shingles). It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases. It is taken by mouth.
Common side effects include headache and vomiting. Severe side effects may include kidney problems. Use in pregnancy appears to be safe. It is a prodrug, which works after being converted to aciclovir in a person’s body.
Valaciclovir was patented in 1987 and came into medical use in 1995. It is available as a generic medication. A month supply in the United Kingdom costs the NHS about £3 as of 2019. In the United States the wholesale cost of this amount is about US$2.80.In 2016 it was the 168th most prescribed medication in the United States with more than 3 million prescriptions.
Valaciclovir is used for the treatment of HSV and VZV infections, including:
- Oral and genital herpes simplex (treatment and prevention)
- Reduction of HSV transmission from people with recurrent infection to uninfected individuals
- Herpes zoster (shingles): the typical dosage for treatment of herpes is 1,000 mg orally three times a day for seven consecutive days.
- Prevention of cytomegalovirus following organ transplantation
- Prevention of herpesviruses in immunocompromised people (such as those undergoing cancer chemotherapy)
- Chickenpox in children ages 2-18)
It has shown promise as a treatment for infectious mononucleosis and is preventively administered in suspected cases of herpes B virus exposure.
Valaciclovir is not recommended in Bell’s palsy due to lack of benefit.
Common adverse drug reactions (≥1% of people) associated with valaciclovir are the same as for aciclovir, its active metabolite. They include: nausea, vomiting, diarrhea and headache. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo, confusion, dizziness, edema, arthralgia, sore throat, constipation, abdominal pain, rash, weakness and/or renal impairment. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenia, leukopenia, tremor, ataxia, encephalopathy, psychotic symptoms, crystalluria, anorexia, fatigue, hepatitis, Stevens–Johnson syndrome, toxic epidermal necrolysis and/or anaphylaxis.
Valaciclovir belongs to a family of molecules. Valaciclovir is a prodrug, an esterified version of aciclovir that has greater oral bioavailability (about 55%) than aciclovir. It is converted by esterases to the active drug, aciclovir, and the amino acid, valine, via hepatic first-pass metabolism. Aciclovir is selectively converted into a monophosphate form by viral thymidine kinase, which is more effective (3000 times) in phosphorylation of aciclovir than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into a disphosphate by cellular guanylate kinase and then into the active triphosphate form, aciclo-GTP, by cellular kinases.
Mechanism of action
Aciclo-GTP, the active triphosphate metabolite of aciclovir, is a very potent inhibitor of viral DNA replication. Aciclo-GTP competitively inhibits and inactivates the viral DNA 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 aciclo-GMP from the chain, which results in inhibition of further activity of DNA polymerase. Aciclo-GTP is fairly rapidly metabolized within the cell, possibly by cellular phosphatases.
Aciclovir 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)
The drug is predominantly active against HSV and, to a lesser extent, VZV. It is only of limited efficacy against EBV and CMV. However, valacyclovir has recently been shown to lower or eliminate the presence of the Epstein–Barr virus in subjects afflicted with acute mononucleosis, leading to a significant decrease in the severity of symptoms. Although it can prevent the establishment of viral latency, acyclovir therapy has not proven effective at eradicating latent viruses in nerve ganglia.
As of 2005, resistance to valaciclovir has not been significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase and mutations to viral thymidine kinase and/or DNA polymerase that alter substrate sensitivity.
It also is used for herpes B virus postexposure prophylaxis.
Valaciclovir was patented in 1987 and came into medical use in 1995. It is available as a generic medication. A month supply in the United Kingdom costs the NHS about £3 as of 2019. In the United States the wholesale cost of this amount is about US$2.80. In 2019, it was the 168th most prescribed medication in the United States with more than 3 million prescriptions.
It is marketed by GlaxoSmithKline under the trade names Valtrex and Zelitrex. Valaciclovir has been available as a generic drug in the U.S. since November 25, 2009.
Valtrex is offered in 500 mg and 1 gram tablets, with the active ingredient valacyclovir hydrochloride. The inactive ingredients include carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide.
Acyclovir (I) was coupled with N-Cbz-L-valine (II) in the presence of DCC and DMAP to afford the Cbz-protected valyl ester (III). The N-benzyloxycarbonyl group of (III) was then removed by either hydrogenation over Pd/C or by transfer hydrogenation in the presence of formic acid. AU 8820978; EP 0308065; EP 0596542; JP 1989068373; JP 1991115284; US 4957924; US 5061708
In an alternative procedure, condensation of L-valine (IV) with methyl acetoacetate (V) in the presence of NaOH produced the enamine-protected valine sodium salt (VI). Condensation of (VI) with the tosylate (VII), (prepared from acyclovir (I) and tosyl chloride) afforded ester (VIII). Then, acidic hydrolysis of the enaminoester moiety of (VIII) furnished the target valine ester. Similar procedures were also reported using omega-mesyl and omega-chloro acyclovir.
The esterification of acyclovir (I) with N-(tert-butoxycarbonyl)-L-valine (II) by means of EDC, TEA and DMAP in DMF gives the corresponding ester (III) which is finally deprotected by means of HCl in water to afford the target valacyclovir.
- Synonyms:Valacyclovir, BW-256U, 256 U 87
- Use:antiviral, prodrug of aciclovir
- Chemical name:l-valine 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester
- MW:324.34 g/mol
- InChI Key:HDOVUKNUBWVHOX-QMMMGPOBSA-N
- Formula:C13H20N6O4 • HCl
- MW:360.80 g/mol
- US 4 957 924 (Burroughs Wellcome; 18.9.1990; GB-prior. 15.8.1987).
- EP 308 065 (Wellcome Found. Ltd; appl. 12.8.1988; GB-prior. 15.8.1987, 5.11.1987).
combination with lamotrigine:
- WO 9 505 179 (Wellcome Found. Ltd; appl. 17.8.1994; GB-prior. 18.8.1993).
- WO 9 213 527 (Wellcome Found. Ltd; appl. 29.1.1992; GB-prior. 30.1.1991, 22.11.1991, 25.11.1991).
medical use for preventing post herpetic neuralgia:
- GB 2 282 759 (SmithKline Beecham; appl. 14.10.1994; GB-prior. 16.10.1993).
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In summary, antiviral therapy alone (acyclovir or valacyclovir) is not recommended in the treatment of Bell’s palsy due to lack of effectiveness of currently available drugs, unnecessary cost, and the potential for drug-related complications.
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- ^ “Valtrex Prescribing Information” (PDF). GlaxoSmithKline. September 2008. Retrieved May 7, 2009.
|Trade names||Valtrex, Zelitrex, others|
|Metabolism||Liver (to aciclovir)|
|Elimination half-life||<30 minutes (valaciclovir);
2.5–3.6 hours (aciclovir)
|Excretion||Kidney 40–50% (aciclovir),
faecal 47% (aciclovir)
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||324.336 g/mol g·mol−1|
|3D model (JSmol)|
//////////////Valacyclovir HCl,hydrochloride salt of L-valyl ester, aciclovir, GlaxoSmithKline ,