Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Valaciclovir: Difference between pages

{{Short description|Antiviral medication}}

{{Use dmy dates|date=October 2022}}

{{Infobox drug

| verifiedrevid =

| image = Valaciclovir structure.svg

| width =

| =

| caption =

| USAN = valacyclovir hydrochloride

<!--Clinical data-->

| =

| tradename = Valtrex, Zelitrex, others

| Drugs.com = {{drugs.com|monograph|valacyclovir-hydrochloride}}

| MedlinePlus = a695010

| DailyMedID = Valacyclovir

| pregnancy_AU = B3

| pregnancy_AU_comment =

| pregnancy_category =

| routes_of_administration = [[Oral administration|By mouth]]

| class = [[Antiviral]]

| ATC_prefix = J05

| ATC_suffix = AB11

| ATC_supplemental =

<!-- Legal status -->

| legal_AU = S4

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = POM

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment = <ref name="Valtrex FDA label">{{cite web | title=Valtrex- valacyclovir hydrochloride tablet, film coated | website=DailyMed | date=14 June 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f8e0d8f8-cb73-4206-a484-88f5c4fbd719 | access-date=22 May 2022}}</ref>

| legal_EU =

| legal_EU_comment =

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = Rx-only

<!--Pharmacokinetic data-->

| metabolism = (to [[aciclovir]])

| metabolites =

| onset =

| elimination_half-life = <30 minutes (valaciclovir);<br />2.5–3.6 hours (aciclovir)

| duration_of_action =

| excretion = [[Kidney]] 40–50% (aciclovir),<br />faecal 47% (aciclovir)

<!--Identifiers-->

| index2_label = as HCl

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 124832-26-4

| CAS_number2 = 124832-27-5

| CAS_supplemental =

| PubChem = 135398742

| PubChem2 = 135398741

| IUPHAR_ligand = 4824

| DrugBank2 = DBSALT000289

| UNII_Ref = {{fdacite||FDA}}

| UNII2 = G447S0T1VC

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D08664

| KEGG2 = D00398

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI2 = 9919

| ChEMBL2 = 1201110

| NIAID_ChemDB = 070982

| PDB_ligand =

| synonyms = valacyclovir

<!--Chemical data-->

| IUPAC_name = 2-[(2-Amino-6-oxo-1''H''-purin-9-yl)methoxy]ethyl (2''S'')-2-amino-3-methylbutanoate

| C=13 | H=20 | N=6 | O=4

| = O=C(OCCOCn1c2N\C(=N/C(=O)c2nc1)N)[C@@H](N)C(C)C

| StdInChI_comment =

| density =

| density_notes =

| melting_point =

| melting_high =

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility =

| sol_units =

| specific_rotation =

<!-- Definition and medical uses -->

'''Valaciclovir''', also spelled '''valacyclovir''', is an [[antiviral medication]] used to treat outbreaks of [[herpes simplex]] or [[herpes zoster]] (shingles).<ref name=AHFS2019/> It is also used to prevent [[cytomegalovirus]] following a [[kidney transplant]] in high risk cases.<ref name=AHFS2019/> It is taken [[by mouth]].<ref name=AHFS2019/>

<!-- Side effects and mechanism -->

Common side effects include [[headache]] and [[vomiting]].<ref name=AHFS2019>{{cite web |title=Valacyclovir Hydrochloride Monograph for Professionals |url=https://www.drugs.com/monograph/valacyclovir-hydrochloride.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=17 March 2019 }}</ref> Severe side effects may include [[kidney problems]].<ref name=AHFS2019/> Use in [[pregnancy]] appears to be safe.<ref name=AHFS2019/> It is a [[prodrug]], which works after being converted to [[aciclovir]] in a person's body.<ref name=AHFS2019/>

<!-- Society and culture -->

Valaciclovir was patented in 1987 and came into medical use in 1995.<ref name=":0">{{cite book | vauthors = Long SS, Pickering LK, Prober CG |title=Principles and Practice of Pediatric Infectious Disease|date=2012|publisher=Elsevier Health Sciences|isbn=978-1437727029|page=1502|url=https://books.google.com/books?id=nQ7-o8JAH7kC&pg=PA1502}}</ref><ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=504 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA504 }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> It is available as a [[generic medication]].<ref name=BNF76>{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=625–626|edition=76}}</ref> In 2021, it was the 114th most commonly prescribed medication in the United States, with more than 5{{nbsp}}million prescriptions.<ref name="Top 300">{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref name="ClinCalc Valacyclovir">{{cite web | title = Valacyclovir - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Valacyclovir | access-date = 14 January 2024}}</ref>

==Medical uses==

[[Image:Valtrex pill.jpg|thumb|Valtrex brand valaciclovir 500mg tablets]]

Valaciclovir is used for the treatment of HSV and VZV infections, including:<ref name="AMH2006">Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006. {{ISBN|0-9757919-2-3}}{{Page needed|date=September 2010}}</ref>

* Oral and genital [[herpes simplex]] (treatment and [[prophylaxis|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&nbsp;mg orally three times a day for seven consecutive days.<ref>{{Cite book | name-list-style = vanc |chapter = Antiviral therapies of shingles in dermatology|title=Herpes zoroster: recent aspects of diagnosis and control| vauthors = Lille HM, Wassilew SW | veditors = Gross G, Doerr H |volume=26|year=2006|page=124| series = Monographs in virology|publisher=[[Karger|Karger Publishers]]|place=Basel (Switzerland)|chapter-url=https://books.google.com/books?id=3Eh51Np2w7IC&q=valacyclovir&pg=PA124|access-date=1 January 2012|isbn=978-3-8055-7982-7}}</ref>

* Prevention of [[cytomegalovirus]] following [[organ transplantation]]

* Prevention of herpesviruses in immunocompromised people (such as those undergoing cancer chemotherapy)<ref name="Cancer">{{cite journal | vauthors = Elad S, Zadik Y, Hewson I, Hovan A, Correa ME, Logan R, Elting LS, Spijkervet FK, Brennan MT | display-authors = 6 |title=A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea |journal=Support Care Cancer |volume=18 |issue=8 |pages=993–1006 |date=August 2010 |pmid=20544224 |doi=10.1007/s00520-010-0900-3|s2cid=2969472 }}</ref>

* Chickenpox in children (ages 2–18)<ref name="Valtrex FDA label" />

It has shown promise as a treatment for [[infectious mononucleosis]]<ref name=balfour2005/><ref name=simon2003>{{Cite journal| vauthors = Simon MW, Deeter RG, Shahan B |date=March 2003 |title=The Effect of Valacyclovir and Prednisolone in Reducing Symptoms of EBV Illness In Children: A Double-Blind, Placebo-Controlled Study |journal=International Pediatrics |volume=18 |issue=3 |pages=164–169 |url=https://www.researchgate.net/publication/237508616 | via=[[ResearchGate]]}}</ref><ref name="pmid17369082" /> and is preventively administered in suspected cases of herpes B virus exposure.<ref name=":3" />

[[Bell's palsy]] does not seem to benefit from using valaciclovir as its only treatment.<ref>{{Cite journal | vauthors = Baugh RF, Basura GJ, Ishii LE, Schwartz SR, Drumheller CM, Burkholder R, Deckard NA, Dawson C, Driscoll C, Gillespie MB, Gurgel RK, Halperin J, Khalid AN, Kumar KA, Micco A, Munsell D, Rosenbaum S, Vaughan W | display-authors = 6 |date=November 2013|title=Clinical practice guideline: Bell's palsy|journal=Otolaryngology–Head and Neck Surgery|volume=149|issue=3_suppl|pages=S1–S27|doi=10.1177/0194599813505967|pmid=24189771|s2cid=36915347 |doi-access=free}}</ref><ref>{{cite journal | vauthors = Gagyor I, Madhok VB, Daly F, Sullivan F | title = Antiviral treatment for Bell's palsy (idiopathic facial paralysis) | journal = Cochrane Database Syst Rev | volume = 2019 | issue = 9| pages = CD001869 | date = September 2019 | pmid = 31486071 | pmc = 6726970 | doi = 10.1002/14651858.CD001869.pub9 }}</ref>

==Adverse effects==

Common [[adverse drug reaction]]s (≥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 (medical)|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 (symptom)|anorexia]], fatigue, [[hepatitis]], [[Stevens–Johnson syndrome]], [[toxic epidermal necrolysis]] and/or [[anaphylaxis]].<ref name="AMH2006" />

== Pharmacology ==

Valaciclovir is a prodrug, an [[ester]]ified version of [[aciclovir]] that has greater oral [[bioavailability]] (about 55%) than aciclovir.<ref name="Valtrex FDA label" /> It is converted by [[esterase]]s 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-[[Guanosine triphosphate|GTP]], by cellular [[kinase]]s.<ref name="Valtrex FDA label" />

=== Mechanism of action ===

Aciclo-GTP, the active triphosphate metabolite of aciclovir, is a very potent inhibitor of [[Viral disease|viral]] [[DNA replication]]. Aciclo-GTP competitively inhibits and inactivates the [[Virus|viral]] [[DNA polymerase]].<ref name="Valtrex FDA label" /> Its monophosphate form also incorporates into the viral DNA, resulting in [[protein biosynthesis|chain termination]]. It has also been shown that the viral enzymes cannot remove aciclo-[[GMP synthase (glutamine—hydrolysing)|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 [[phosphatase]]s.<ref>{{cite web |url=http://www.uscnk.us/protein-antibody-elisa/Valaciclovir-%28VCV%29-V511.htm |title= Valaciclovir (VCV) - USCN LIFE SCIENCE INC|website=www.uscnk.us |archive-url=https://archive.today/20141203154533/http://www.uscnk.us/protein-antibody-elisa/Valaciclovir-(VCV)-V511.htm |archive-date= 3 December 2014 |url-status=live}}</ref>

Aciclovir is active against most species in the [[herpesvirus]] family. In descending order of activity:<ref name="OBrien1989">{{Cite journal|author=O'Brien JJ, Campoli-Richards DM |title=Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy |journal=Drugs |volume=37 |issue=3 |pages=233–309 |date=March 1989 |pmid=2653790 |doi= 10.2165/00003495-198937030-00002|s2cid=240858022 |doi-access=free }}</ref>

* [[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, valaciclovir has 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.<ref name=balfour2005>{{cite conference | vauthors = Balfour HH, Hokanson KM, Schacherer RM | title = A controlled trial of valacyclovir in infectious mononucleosis. | conference = 45th Interscience Conference on Antimicrobial Agents and Chemotherapy | location = Washington, DC | date = December 2005 | pages = 16–19 | id = Abstract V1392 }}</ref><ref name=simon2003 /><ref name="pmid17369082">{{Cite journal | vauthors = Balfour HH, Hokanson KM, Schacherer RM, Fietzer CM, Schmeling DO, Holman CJ, Vezina HE, Brundage RC | display-authors = 6 |title=A virologic pilot study of valacyclovir in infectious mononucleosis |journal=Journal of Clinical Virology |volume=39 |issue=1 |pages=16–21 |date=May 2007 |pmid=17369082 |doi=10.1016/j.jcv.2007.02.002 }}</ref> Valaciclovir and acyclovir act by inhibiting viral DNA replication, but as of 2016 there was little evidence that they are effective against Epstein–Barr virus.<ref name="pmid27933614">{{cite journal | vauthors=De Paor M, O'Brien K, Smith SM | title=Antiviral agents for infectious mononucleosis (glandular fever) | journal=[[Cochrane Library#The Cochrane Database of Systematic Reviews|The Cochrane Database of Systematic Reviews]] | volume=2016 | issue=12 | pages=CD011487 | year=2016 | doi = 10.1002/14651858.CD011487.pub2 | pmc=6463965 | pmid=27933614}}</ref> Acyclovir therapy does prevent [[Virus latency|viral latency]], but has not proven effective at eradicating latent viruses in [[ganglion|nerve ganglia]].<ref name="OBrien1989">{{Cite journal|author=O'Brien JJ, Campoli-Richards DM |title=Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy |journal=Drugs |volume=37 |issue=3 |pages=233–309 |date=March 1989 |pmid=2653790 |doi= 10.2165/00003495-198937030-00002|s2cid=240858022 |doi-access=free }}</ref>

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.<ref name="Martindale34">{{Cite book| veditors = Sweetman SC |title=Martindale: the complete drug reference |edition=34th |publisher=Pharmaceutical Press |location=London |year=2005 |isbn=0-85369-550-4 |oclc=56903116}}{{Page needed|date=September 2010}}</ref>

It also is used for [[herpes B virus]] postexposure prophylaxis.<ref name=":3">{{cite web | title=Herpes B Virus: Information For Healthcare Providers | website=U.S. [[Centers for Disease Control and Prevention]] (CDC) | date=31 January 2019 | url=https://www.cdc.gov/herpesbvirus/healthcare-providers.html | access-date=22 May 2022}}</ref><ref>{{cite journal | vauthors = Cohen JI, Davenport DS, Stewart JA, Deitchman S, Hilliard JK, Chapman LE | title = Recommendations for prevention of and therapy for exposure to B virus (cercopithecine herpesvirus 1) | journal = Clin Infect Dis | volume = 35 | issue = 10 | pages = 1191–203 | date = November 2002 | pmid = 12410479 | doi = 10.1086/344754 | s2cid = 4652818 | doi-access = free }}</ref>

== Chemistry ==

Details of the synthesis of valaciclovir were first published by scientists from the [[Wellcome Foundation]].

:[[File:Valaciclovir sythesis.svg|650px]]

Aciclovir was esterified with a [[carboxybenzyl]] [[protecting group|protected]] [[valine]], using [[dicyclohexylcarbodiimide]] as the [[Dehydration reaction|dehydrating agent]]. In the final step, the protecting group was removed by [[hydrogenation]] using a palladium on alumina catalyst.<ref>{{cite patent |country=EP |number=308065 |status=patent |pubdate=1989-03-22 |fdate=1988-08-12 |pridate=1987-08-15 |invent1=Krenitsky, Thomas Anthony |invent2=Beauchamp, Lilia Marie |title=Therapeutic nucleosides |assign1=Wellcome Foundation}}</ref><ref>{{cite book |doi=10.1016/B978-0-12-411492-0.00034-1 |doi-access=free |chapter=34: Antiviral Drugs |title=Synthesis of Best-Seller Drugs |year=2016 | vauthors = Vardanyan R, Hruby V |page=709 |isbn=9780124114920 |s2cid=75449475 }}</ref>

== History ==

Valaciclovir was patented in 1987 and came into medical use in 1995.<ref name=":0" /><ref name="Fis2006" /> It is available as a [[generic medication]].<ref name="BNF76" /> In 2021, it was the 114th most commonly prescribed medication in the United States, with more than 5{{nbsp}}million prescriptions.<ref name="Top 300" /><ref name="ClinCalc Valacyclovir" />

==Society and culture==

=== Brand names ===

It is marketed by [[GlaxoSmithKline]] under the brand names Valtrex<ref name="Valtrex FDA label" /> and Zelitrex. Valaciclovir has been available as a [[generic drug]] in the U.S. since November 2009.<ref>{{Cite news|url=https://www.wsj.com/articles/SB125931422280866181|title=Ranbaxy Launches Generic Valtrex in U.S.| vauthors = Ahmed R |date=27 November 2009|work=[[The Wall Street Journal]]|access-date=16 January 2010}}</ref>

==References==

{{Reflist}}

{{Antivirals}}

{{GlaxoSmithKline}}

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[[Category:Amino acid derivatives]]

[[Category:Anti-herpes virus drugs]]

[[Category:Drugs developed by GSK plc]]

[[Category:Carboxylate esters]]

[[Category:Ethers]]

[[Category:Prodrugs]]

[[Category:Purines]]

[[Category:Herpes]]

[[Category:World Health Organization essential medicines]]

[[Category:Wikipedia medicine articles ready to translate]]