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

{{Short description|Antiviral medication used against herpes, chickenpox, and shingles}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

<!-- Please do not change "aciclovir" to "acyclovir". "Aciclovir" is the International Nonproprietary Name, and is thus preferred. -->

| verifiedrevid =

| image = Aciclovir 2D structure.svg

| alt =

| image2 = .png

| alt2 =

| USAN = acyclovir

| BAN = acyclovir

<!--Clinical data-->

| pronounce = {{IPAc-en|eɪ|ˈ|s|aɪ|k|l|oʊ-|v|ɪər}}

| tradename = Zovirax, others<ref name=Names/>

| Drugs.com = {{ubl

| Acyclovir {{drugs.com|monograph|acyclovir}}

| Acyclovir topical {{drugs.com|monograph|acyclovir-topical}}

}}

| DailyMedID = Acyclovir

| pregnancy_AU = B3

| routes_of_administration = [[intravenous therapy|Intravenous]], [[Oral administration|by mouth]], [[Topical medication|topical]], [[Ophthalmic drug administration|eye ointment]]

| ATC_prefix = J05

| ATC_suffix = AB01

| ATC_supplemental = {{ATC|D06|BB03}}, {{ATC|S01|AD03}}, {{ATC|D06|BB53}}

<!-- Legal data -->

| legal_AU = S4

| legal_AU_comment =

| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | title=Skin health | website=[[Health Canada]] | date=9 May 2018 | url=https://www.canada.ca/en/services/health/drug-health-products/drug-medical-device-highlights-2017/approved-drugs/skin-health.html | access-date=13 April 2024}}</ref>

| legal_UK = POM

| legal_UK_comment =

| legal_status =

<!--Pharmacokinetic data-->

| bioavailability = 15–20% (by mouth)<ref name=MSR>{{cite web|title=Zovirax (acyclovir) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=5 February 2014|url=http://reference.medscape.com/drug/zovirax-acyclovir-342601#showall|url-status=live|archive-url=https://web.archive.org/web/20140219005955/http://reference.medscape.com/drug/zovirax-acyclovir-342601#showall|archive-date=19 February 2014}}</ref>

| protein_bound = 9–33%

| metabolism =

| elimination_half-life = hours

| excretion = [[]]

<!--Identifiers-->

| IUPHAR_ligand = 4829

| PubChemSubstance = 46506002

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| KEGG2_Ref = {{keggcite|changed|kegg}}

| KEGG2 = C06810

| PDB_ligand = AC2

<!--Chemical data-->

| IUPAC_name = 2-amino-1,9-dihydro-9-((2-hydroxyethoxy)methyl)-3''H''-purin-6-one

| C=8 | H=11 | N=5 | O=3

| = O=C2/N=C(\Nc1n(cnc12)COCCO)N

| synonyms =

<!-- Definition and medical uses -->

'''Aciclovir''', also known as '''acyclovir''',<ref>{{cite web | vauthors = Kevin ES |title=The Aciclovir |url=https://deutschemedz.de/aciclovir/ |publisher=Kevin |language=DE |access-date=25 May 2017}}</ref> is an [[antiviral medication]].<ref name=deClercq2005>{{cite news| vauthors = de Clercq E, Field HJ | publication-date = January 2006 | date = 5 October 2005 | title = Antiviral prodrugs – the development of successful prodrug strategies for antiviral chemotherapy| periodical = [[British Journal of Pharmacology]] | publisher = Wiley-Blackwell| volume = 147 | issue = 1| pages = 1–11| pmid= 16284630 | pmc= 1615839 | doi = 10.1038/sj.bjp.0706446}}</ref> It is primarily used for the treatment of [[herpes simplex virus]] infections, [[chickenpox]], and [[shingles]].<ref name=AHFS2015/> Other uses include prevention of [[cytomegalovirus]] infections following transplant and severe complications of [[Epstein–Barr virus]] infection.<ref name=AHFS2015/><ref name="pmid20739216">{{cite journal | vauthors = Rafailidis PI, Mavros MN, Kapaskelis A, Falagas ME | title = Antiviral treatment for severe EBV infections in apparently immunocompetent patients | journal = Journal of Clinical Virology | volume = 49 | issue = 3 | pages = 151–157 | date = November 2010 | pmid = 20739216 | doi = 10.1016/j.jcv.2010.07.008 }}</ref> It can be taken by mouth, applied as a cream, or [[intravenously|injected]].<ref name=AHFS2015>{{cite web|title=Acyclovir|url=https://www.drugs.com/monograph/acyclovir.html|publisher=The American Society of Health-System Pharmacists|access-date=Jan 1, 2015|url-status=live|archive-url=https://web.archive.org/web/20150105113809/http://www.drugs.com/monograph/acyclovir.html|archive-date=2015-01-05}}</ref>

<!-- Side effects -->

Common side effects include nausea and diarrhea.<ref name=AHFS2015/> Potentially serious side effects include kidney problems and [[thrombocytopenia|low platelet]]s.<ref name=AHFS2015/> Greater care is recommended in those with poor liver or kidney function.<ref name=AHFS2015/> It is generally considered safe for use in [[pregnancy]] with no harm having been observed.<ref name=AHFS2015/><ref>{{cite web|title=Prescribing medicines in pregnancy database|url=http://www.tga.gov.au/hp/medicines-pregnancy.htm|work=Australian Government|access-date=22 April 2014|date=3 March 2014|url-status=live|archive-url=https://web.archive.org/web/20140408040902/http://www.tga.gov.au/hp/medicines-pregnancy.htm|archive-date=8 April 2014}}</ref> It appears to be safe during [[breastfeeding]].<ref name=Ric2015>{{cite book| vauthors = Hamilton R |title=Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition|date=2015|publisher=Jones & Bartlett Learning|isbn=9781284057560|page=59}}</ref><ref>{{cite web|title=Acyclovir use while Breastfeeding|url=https://www.drugs.com/breastfeeding/acyclovir.html|access-date=8 March 2016|date=Mar 10, 2015|quote=Even with the highest maternal dosages, the dosage of acyclovir in milk is only about 1% of a typical infant dosage and would not be expected to cause any adverse effects in breastfed infants|url-status=live|archive-url=https://web.archive.org/web/20160305200238/http://www.drugs.com/breastfeeding/acyclovir.html|archive-date=5 March 2016}}</ref> Aciclovir is a [[nucleoside analogue]] that mimics [[guanosine]].<ref name=AHFS2015/> It works by decreasing the production of the virus's [[DNA]].<ref name=AHFS2015/>

<!-- Society and culture -->

Aciclovir was patented in 1974 by [[Burroughs Wellcome]], and approved for medical use in 1981.<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="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> It is available as a [[generic medication]] and is marketed under many brand names worldwide.<ref name=Names>{{cite web|title=Aciclovir|url=https://www.drugs.com/international/aciclovir.html|website=Drugs.com|access-date=6 September 2015|url-status=live|archive-url=https://web.archive.org/web/20150923225253/http://www.drugs.com/international/aciclovir.html|archive-date=23 September 2015}}</ref> In 2022, it was the 134th most commonly prescribed medication in the United States, with more than 4{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Acyclovir Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Acyclovir | access-date = 30 August 2024 }}</ref>

==Medical use==

[[File:Pile of round aciclovir tablets.jpg|thumb|400 mg pills of aciclovir]]

Aciclovir is used for the treatment of [[herpes simplex virus]] (HSV) and [[varicella zoster virus]] infections, including:<ref name =MSR/><ref name=AMH>{{cite book | title = Australian Medicines Handbook | year = 2013 | publisher = The Australian Medicines Handbook Unit Trust | isbn = 978-0-9805790-9-3 | edition = 2013 | place = Adelaide | editor = Rossi, S }}</ref><ref name = BNF>{{cite book | last1 = Joint Formulary Committee | title = British National Formulary (BNF) | year = 2013 | url = https://archive.org/details/bnf65britishnati0000unse | isbn = 978-0-85711-084-8 | edition = 65 | location = London | publisher = Pharmaceutical Press | url-access = registration }}</ref>

* Genital [[herpes simplex]] (treatment and [[prophylaxis|prevention]])

* [[Neonatal herpes simplex]]

* Herpes simplex labialis ([[cold sores]])

* [[Shingles]]

* Acute [[chickenpox]] in [[immunodeficiency|immunocompromised]] [[patient]]s

* [[Herpes simplex encephalitis]]

* Acute [[mucocutaneous]] HSV infections in immunocompromised patients

* [[Herpes of the eye]] and herpes simplex [[blepharitis]] (a chronic (long-term) form of herpes eye infection)

* Prevention of herpes viruses in immunocompromised people (such as people 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 | title = A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea | journal = Supportive Care in Cancer | volume = 18 | issue = 8 | pages = 993–1006 | date = August 2010 | pmid = 20544224 | doi = 10.1007/s00520-010-0900-3 | s2cid = 2969472 }}</ref>

Its effectiveness in treating [[Epstein–Barr virus]] infections is less clear.<ref name=AHFS2015/> It has not been found to be useful for [[infectious mononucleosis]] due to Epstein-Barr virus.<ref>{{cite journal | vauthors = Gershburg E, Pagano JS | title = Epstein-Barr virus infections: prospects for treatment | journal = The Journal of Antimicrobial Chemotherapy | volume = 56 | issue = 2 | pages = 277–281 | date = August 2005 | pmid = 16006448 | doi = 10.1093/jac/dki240 | citeseerx = 10.1.1.320.6721 }}</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, they are expensive, they risk causing resistance to antiviral agents, and (in 1% to 10% of cases) can cause unpleasant [[side effect]]s.<ref name="pmid27933614">{{cite journal | vauthors = De Paor M, O'Brien K, Fahey T, Smith SM | title = Antiviral agents for infectious mononucleosis (glandular fever) | journal = The Cochrane Database of Systematic Reviews | volume = 2016 | issue = 12 | pages = CD011487 | date = December 2016 | pmid = 27933614 | pmc = 6463965 | doi = 10.1002/14651858.CD011487.pub2 }}</ref>

Aciclovir taken by mouth does not appear to decrease the risk of pain after shingles.<ref>{{cite journal | vauthors = Chen N, Li Q, Yang J, Zhou M, Zhou D, He L | title = Antiviral treatment for preventing postherpetic neuralgia | journal = The Cochrane Database of Systematic Reviews | volume = 2014 | issue = 2 | pages = CD006866 | date = February 2014 | pmid = 24500927 | doi = 10.1002/14651858.CD006866.pub3 | pmc = 10583132 }}</ref> In those with herpes of the eye, aciclovir may be more effective and safer than [[idoxuridine]].<ref name=Wilhelmus2015>{{cite journal | vauthors = Wilhelmus KR | title = Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD002898 | date = January 2015 | issue = 1 | pmid = 25879115 | pmc = 4443501 | doi = 10.1002/14651858.CD002898.pub5 }}</ref> It is not clear if aciclovir eye drops are more effective than [[brivudine]] eye drops.<ref name=Wilhelmus2015 />

[[Intravenous]] aciclovir is effective to treat severe medical conditions caused by different species of the herpes virus family, including severe localized infections of herpes virus, severe genital herpes, [[chickenpox]] and [[herpesviral encephalitis]]. It is also effective in systemic or traumatic herpes infections, eczema herpeticum and [[herpesviral meningitis]].

Reviews of research dating from the 1980s show there is some effect in reducing the number and duration of lesions if aciclovir is applied at an early stage of an outbreak.<ref>{{cite journal | vauthors = Worrall G | title = Acyclovir in recurrent herpes labialis | journal = BMJ | volume = 312 | issue = 7022 | pages = 6 | date = January 1996 | pmid = 8555890 | pmc = 2349724 | doi = 10.1136/bmj.312.7022.6 | url = http://www.bmj.com/cgi/content/full/312/7022/6 | url-status = live | archive-url = https://web.archive.org/web/20070515183925/http://www.bmj.com/cgi/content/full/312/7022/6 | archive-date = 2007-05-15 }} – Editorial</ref> Research shows effectiveness of topical aciclovir in both the early and late stages of the outbreak as well as improving methodologically and in terms of statistical certainty from previous studies.<ref>{{cite journal | vauthors = Spruance SL, Nett R, Marbury T, Wolff R, Johnson J, Spaulding T | title = Acyclovir cream for treatment of herpes simplex labialis: results of two randomized, double-blind, vehicle-controlled, multicenter clinical trials | journal = Antimicrobial Agents and Chemotherapy | volume = 46 | issue = 7 | pages = 2238–2243 | date = July 2002 | pmid = 12069980 | pmc = 127288 | doi = 10.1128/aac.46.7.2238-2243.2002 }}</ref> Aciclovir trials show that this agent has no role in preventing [[HIV]] transmission, but it can help slow HIV disease progression in people not taking [[Management of HIV/AIDS|anti-retroviral therapy (ART)]]. This finding emphasizes the importance of testing simple, inexpensive non-ART strategies, such as aciclovir and [[Trimethoprim/sulfamethoxazole|cotrimoxazole]], in people with HIV.<ref>{{cite journal | vauthors = Mascolinli M, Kort R | title = 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention: summary of key research and implications for policy and practice - biomedical prevention | journal = Journal of the International AIDS Society | volume = 13 | issue = Suppl 1 | pages = S4 | date = June 2010 | pmid = 20519025 | pmc = 2880255 | doi = 10.1186/1758-2652-13-S1-S4 | doi-access = free }}</ref>

===Pregnancy===

The CDC and others have declared that during severe recurrent or first episodes of genital herpes, aciclovir may be used.<ref>{{cite journal | vauthors = | title = Drugs for non-HIV viral infections | journal = Treatment Guidelines from the Medical Letter | volume = 3 | issue = 32 | pages = 23–32 | date = April 2005 | pmid = 15767977 }}</ref> For severe HSV infections (especially disseminated HSV), IV aciclovir may also be used.<ref name="pmid19357635">{{cite journal | vauthors = Kaplan JE, Benson C, Holmes KK, Brooks JT, Pau A, Masur H | title = Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America | journal = MMWR. Recommendations and Reports| volume = 58 | issue = RR-4 | pages = 1–207; quiz CE1–4 | date = April 2009 | pmid = 19357635 | doi = | url = https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5804a1.htm }}</ref>

Studies in mice, rabbits and rats (with doses more than 10 times the equivalent of that used in humans) given during [[organogenesis]] have failed to demonstrate birth defects.<ref name =TGA/> Studies in rats in which they were given the equivalent to 63 times the standard steady-state humans concentrations of the drug<ref group = Note>Subject to the same conditions as before</ref> on day 10 of gestation showed head and tail anomalies.<ref name = TGA/>

Aciclovir is recommended by the CDC for treatment of [[varicella]] during pregnancy, especially during the second and third trimesters.<ref>{{cite book | author = Centers for Disease Control and Prevention. | title = Epidemiology and prevention of vaccine-preventable diseases. | edition = 9th | publisher = Public Health Foundation | date = January 2006 | pages = 171–192 }}</ref>

Aciclovir is excreted in the breast milk, therefore it is recommended that caution should be used in breast-feeding women. It has been shown in limited test studies that the nursing infant is exposed to approximately 0.3&nbsp;mg/kg/day following oral administration of aciclovir to the mother. If nursing mothers have herpetic lesions near or on the breast, breast-feeding should be avoided.<ref name=Label>{{cite web | publisher = FDA | work = GSK | url =http://www.accessdata.fda.gov/drugsatfda_docs/label/2001/18828s26s27lbl.pdf | title = Acyclovir label | archive-url = https://web.archive.org/web/20170908162359/https://www.accessdata.fda.gov/drugsatfda_docs/label/2001/18828s26s27lbl.pdf | archive-date=2017-09-08 | date = 2005 }}</ref><ref name="Gartner_2005">{{cite journal | vauthors = Gartner LM, Morton J, Lawrence RA, Naylor AJ, O'Hare D, Schanler RJ, Eidelman AI | title = Breastfeeding and the use of human milk | journal = Pediatrics | volume = 115 | issue = 2 | pages = 496–506 | date = February 2005 | pmid = 15687461 | doi = 10.1542/peds.2004-2491 | s2cid = 5791615 | doi-access = free }}</ref>

== Adverse effects ==

===Systemic therapy===

Common [[adverse drug reaction]]s (≥1% of patients) associated with systemic aciclovir therapy (oral or IV) include nausea, vomiting, diarrhea, [[encephalopathy]] (with IV use only), injection site reactions (with IV use only) and headache. In high doses, [[hallucination]]s have been reported. Infrequent adverse effects (0.1–1% of patients) include agitation, [[vertigo (medical)|vertigo]], confusion, dizziness, [[oedema]], [[arthralgia]], sore throat, constipation, abdominal pain, hair loss, rash and weakness. Rare adverse effects (<0.1% of patients) include coma, seizures, [[neutropenia]], [[leukopenia]], [[crystalluria]], [[anorexia (symptom)|anorexia]], fatigue, [[hepatitis]], [[Stevens–Johnson syndrome]], [[toxic epidermal necrolysis]], [[thrombotic thrombocytopenic purpura]], [[anaphylaxis]],<ref name="AMH" /> and [[Cotard's syndrome]].

Intravenous aciclovir may cause reversible [[nephrotoxicity]] in up to 5% to 10% of patients because of precipitation of aciclovir crystals in the kidney. Aciclovir crystalline nephropathy is more common when aciclovir is given as a rapid infusion and in patients with dehydration and preexisting renal impairment. Adequate hydration, a slower rate of infusion, and dosing based on renal function may reduce this risk.<ref name=razonable>{{cite journal | vauthors = Razonable RR | title = Antiviral drugs for viruses other than human immunodeficiency virus | journal = Mayo Clinic Proceedings | volume = 86 | issue = 10 | pages = 1009–1026 | date = October 2011 | pmid = 21964179 | pmc = 3184032 | doi = 10.4065/mcp.2011.0309 }}</ref><ref name="pmid6285711">{{cite journal | vauthors = Brigden D, Rosling AE, Woods NC | title = Renal function after acyclovir intravenous injection | journal = The American Journal of Medicine | volume = 73 | issue = 1A | pages = 182–185 | date = July 1982 | pmid = 6285711 | doi = 10.1016/0002-9343(82)90087-0 }}</ref><ref name="pmid3376977">{{cite journal | vauthors = Sawyer MH, Webb DE, Balow JE, Straus SE | title = Acyclovir-induced renal failure. Clinical course and histology | journal = The American Journal of Medicine | volume = 84 | issue = 6 | pages = 1067–1071 | date = June 1988 | pmid = 3376977 | doi = 10.1016/0002-9343(88)90313-0 | url = https://zenodo.org/record/1253778 }}</ref>

The aciclovir metabolite [[9-Carboxymethoxymethylguanine]] (9-CMMG) has been shown to play a role in neurological adverse events, particularly in older people and those with reduced renal function.<ref>{{cite journal | vauthors = Helldén A, Odar-Cederlöf I, Diener P, Barkholt L, Medin C, Svensson JO, Säwe J, Ståhle L | title = High serum concentrations of the acyclovir main metabolite 9-carboxymethoxymethylguanine in renal failure patients with acyclovir-related neuropsychiatric side effects: an observational study | journal = Nephrology, Dialysis, Transplantation | volume = 18 | issue = 6 | pages = 1135–1141 | date = June 2003 | pmid = 12748346 | doi = 10.1093/ndt/gfg119 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Berry L, Venkatesan P | title = Aciclovir-induced neurotoxicity: Utility of CSF and serum CMMG levels in diagnosis | journal = Journal of Clinical Virology | volume = 61 | issue = 4 | pages = 608–610 | date = December 2014 | pmid = 25440915 | doi = 10.1016/j.jcv.2014.09.001 }}</ref><ref>{{cite journal | vauthors = Chowdhury MA, Derar N, Hasan S, Hinch B, Ratnam S, Assaly R | title = Acyclovir-Induced Neurotoxicity: A Case Report and Review of Literature | journal = American Journal of Therapeutics | volume = 23 | issue = 3 | pages = e941–e943 | date = 2016 | pmid = 24942005 | doi = 10.1097/MJT.0000000000000093 | s2cid = 32983100 }}</ref>

===Topical therapy===

Aciclovir topical cream is commonly associated (≥1% of patients) with: dry or flaking skin or transient stinging/burning sensations. Infrequent adverse effects include [[erythema]] or itch.<ref name="AMH" /> When applied to the eye, aciclovir is commonly associated (≥1% of patients) with transient mild stinging. Infrequently (0.1–1% of patients), ophthalmic aciclovir is associated with superficial [[punctate keratitis]] or allergic reactions.<ref name="AMH" />

==Drug interactions==

[[Ketoconazole]]: In-vitro replication studies have found a synergistic, dose-dependent antiviral activity against HSV-1 and HSV-2 when given with aciclovir. However, this effect has not been clinically established and more studies need to be done to evaluate the true potential of this synergy.<ref>{{cite journal | vauthors = Pottage JC, Kessler HA, Goodrich JM, Chase R, Benson CA, Kapell K, Levin S | title = In vitro activity of ketoconazole against herpes simplex virus | journal = Antimicrobial Agents and Chemotherapy | volume = 30 | issue = 2 | pages = 215–219 | date = August 1986 | pmid = 3021048 | pmc = 180521 | doi = 10.1128/aac.30.2.215 }}</ref>

[[Probenecid]]: Reports of increased half life of aciclovir, as well as decreased urinary excretion and renal clearance have been shown in studies where probenecid is given simultaneously with aciclovir.<ref name=Label/>

[[Interferon]]: Synergistic effects when administered with aciclovir and caution should be taken when administering aciclovir to patients receiving IV interferon.<ref>GlaxoSmithKline. Zovirax® (acyclovir sodium) for injection prescribing information. Research Triangle Park, NC; 2003 Nov</ref>

[[Zidovudine]]: Although administered often with aciclovir in HIV patients, [[neurotoxicity]] has been reported in at least one patient who presented with extreme drowsiness and lethargy 30–60 days after receiving IV aciclovir; symptoms resolved when aciclovir was discontinued.<ref>{{cite journal | vauthors = Bach MC | title = Possible drug interaction during therapy with azidothymidine and acyclovir for AIDS | journal = The New England Journal of Medicine | volume = 316 | issue = 9 | pages = 547 | date = February 1987 | pmid = 3468354 | doi = 10.1056/NEJM198702263160912 }}</ref>

==Detection in biological fluids==

Aciclovir may be quantitated in plasma or serum to monitor for drug accumulation in patients with renal dysfunction or to confirm a diagnosis of poisoning in acute overdose victims.<ref name="DT8">{{cite book| vauthors = Baselt RC |title=Disposition of toxic drugs and chemicals in man|year=2008|publisher=Biomedical Publications|location=Foster City, CA|isbn=9780962652370|pages=29–31|edition=8th}}</ref>

==Mechanism of action==

[[Image:Guanosine aciclovir comparison.svg|200px|thumb|Structures of [[guanosine]] and aciclovir compared]]

[[File:Acyclovir.svg|thumb|370x370px|Mechanisms (HSV DNA polymerase inhibition and HSV DNA incorporation) of acyclovir action]]

Aciclovir is converted by viral [[thymidine kinase]] to aciclovir monophosphate, which is then converted by host cell [[kinases]] to aciclovir triphosphate (ACV-TP, also known as aciclo-[[Guanosine triphosphate|GTP]]).<ref name = TGA/> ACV-TP is a very potent inhibitor of [[Viral disease|viral]] [[DNA replication]]. ACV-TP competitively inhibits and inactivates the viral [[DNA polymerase]].<ref>{{cite web|url=https://gsksource.com/pharma/content/gsk/source/us/en/brands/valtrex.html|title=VALTREX (valacyclovir hydrochloride) Caplets -GSKSource|website=gsksource.com|access-date=2019-08-02}}</ref> Its monophosphate form also incorporates into the viral DNA, resulting in [[protein biosynthesis|chain termination]].<ref name=TGA>{{cite web|title=PRODUCT INFORMATION NAME OF THE DRUG OZVIR TABLETS|work=TGA eBusiness Services|publisher=Ranbaxy Australia Pty Ltd|date=26 August 2011|access-date=6 February 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-00595-3|format=PDF|url-status=live|archive-url=https://web.archive.org/web/20160820205438/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-00595-3|archive-date=20 August 2016}}</ref><ref name=DM>{{cite web|title=Acyclovir (acyclovir) Capsule Acyclovir (acyclovir) Tablet [Genpharm Inc.]|work=DailyMed|publisher=Genpharm Inc.|date=November 2006|access-date=5 February 2014|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=12ea5042-8ea6-4ee9-a734-684a73edb373|url-status=live|archive-url=https://web.archive.org/web/20140221224423/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=12ea5042-8ea6-4ee9-a734-684a73edb373|archive-date=21 February 2014}}</ref><ref name=EMC>{{cite web|title=Aciclovir Tablets BP 400mg - Summary of Product Characteristics (SPC)|work=electronic Medicines Compendium|publisher=Actavis UK Ltd|date=20 August 2012|access-date=5 February 2014|url=http://www.medicines.org.uk/emc/medicine/23721/SPC/Aciclovir+Tablets+BP+400mg/|url-status=live|archive-url=https://web.archive.org/web/20140222201708/http://www.medicines.org.uk/EMC/medicine/23721/SPC/Aciclovir+Tablets+BP+400mg|archive-date=22 February 2014}}</ref>

===Resistance===

Resistance to aciclovir is rare in people with healthy immune systems, but is more common (up to 10%) in people with immunodeficiencies on chronic antiviral prophylaxis (transplant recipients, people with [[AIDS|acquired immunodeficiency syndrome]] due to HIV infection). Mechanisms of resistance in HSV include deficient viral thymidine kinase; and mutations to viral thymidine kinase or DNA polymerase, altering substrate sensitivity.<ref name="Martindale">{{cite book|title=Martindale: The Complete Drug Reference|chapter=Aciclovir|date=7 August 2013|publisher=Pharmaceutical Press|editor=Sweetman, S|access-date=6 February 2014|chapter-url=http://www.medicinescomplete.com/mc/martindale/current/ms-1682-a.htm|location=London, UK}}</ref><ref>{{cite journal | vauthors = Piret J, Boivin G | title = Resistance of herpes simplex viruses to nucleoside analogues: mechanisms, prevalence, and management | journal = Antimicrobial Agents and Chemotherapy | volume = 55 | issue = 2 | pages = 459–472 | date = February 2011 | pmid = 21078929 | pmc = 3028810 | doi = 10.1128/AAC.00615-10 }}</ref>

===Microbiology===

[[File:VZV plaques.jpg|thumb|right|Varicella zoster virus-produced plaques in monolayers of [[MRC-5|{{nowrap|MRC-5 cells}}]]. When the virus was reproducing

each well contained different amounts of the antiviral drug aciclovir. By counting the plaques (holes formed by the virus in the layer of cells) the potency of the aciclovir to the virus was calculated.]]

Aciclovir is active against most species in the [[herpesvirus]] family. In descending order of activity:<ref name="OBrien1989">{{cite journal | vauthors = 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><ref>{{cite journal | vauthors = Wagstaff AJ, Faulds D, Goa KL | title = Aciclovir. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic efficacy | journal = Drugs | volume = 47 | issue = 1 | pages = 153–205 | date = January 1994 | pmid = 7510619 | doi = 10.2165/00003495-199447010-00009 | doi-access = free }}</ref>

* [[Herpes simplex virus]] type I (HSV-1)

* [[Herpes simplex virus]] type II (HSV-2)

* [[Varicella zoster virus]]

* [[Epstein–Barr virus]]

* [[Human cytomegalovirus]] – least activity

== Pharmacokinetics ==

Aciclovir is poorly water-soluble and has poor oral [[bioavailability]] (15–30%), hence [[intravenous]] administration is necessary if high concentrations are required. When orally administered, peak plasma concentration occurs after 1–2 hours. According to the Biopharmaceutical Classification System, aciclovir is a Class III drug, i.e., soluble with low intestinal permeability.<ref name="J.R. Karmokeretal.2019">{{cite journal | vauthors = Karmoker JR, Hasan I, Ahmed N, Saifuddin M, Reza MS |year=2019 |title=Development and Optimization of Acyclovir Loaded Mucoadhesive Microspheres by Box -Behnken Design |journal=Dhaka University Journal of Pharmaceutical Sciences |volume=18|issue=1|pages=1–12 |doi=10.3329/dujps.v18i1.41421|doi-access=free }}</ref> Aciclovir has a high distribution rate; protein binding is reported to range from 9 to 33%.<ref name="emc SPC">{{cite web|url=https://www.medicines.org.uk/EMC/medicine/23721/SPC/Aciclovir+Tablets+BP+400mg|title=Aciclovir Tablets BP 400mg - Summary of Product Characteristics (SmPC) - (emc)|website=www.medicines.org.uk}}</ref> The [[elimination half-life]] (t_1/2) of aciclovir depends according to age group; neonates have a t_1/2 of 4 hours, children 1–12 years have a t_1/2 of 2–3 hours whereas adults have a t_1/2 of 3 hours.<ref name = MSR/>

== Chemistry ==

Details of the synthesis of aciclovir were first published by scientists from the [[University at Buffalo]].<ref name="Schaffer JMC">{{cite journal | vauthors = Schaeffer HJ, Gurwara S, Vince R, Bittner S | title = Novel substrate of adenosine deaminase | journal = Journal of Medicinal Chemistry | volume = 14 | issue = 4 | pages = 367–369 | date = April 1971 | pmid = 5553754 | doi = 10.1021/jm00286a024 }}</ref>

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

In the first step shown, 2,6-dichloro[[purine]] was [[alkylation|alkylated]] with 1-benzoyloxy-2-chloromethoxyethane. The chlorine group at the 6-position of the heterocyclic ring is more reactive than the chlorine at the 2-position, hence it can be selectively replaced by an [[amino group]], which was then converted to an amide using [[nitrous acid]]. Finally, the remaining chlorine was replaced by the amino group of aciclovir using ammonia in methanol.<ref>{{cite patent |country=US |number=4199574 |status=patent |pubdate=1980-04-22 |fdate=1976-03-01 |pridate=1974-09-02 |inventor = Schaeffer HJ |title=Methods and compositions for treating viral infections and guanine acyclic nucleosides |assign1=Burroughs Wellcome | postscript = . }}</ref> This synthesis and other methods for preparing the compound have been reviewed.<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 |pages=706–708 |publisher=Academic Press |isbn=9780124114920 |s2cid=75449475 }}</ref>

==History==

Aciclovir was seen as the start of a new era in antiviral therapy, as it is extremely selective and low in [[cytotoxicity]].<ref name=deClercq2005/> Since discovery in mid 1970s, it has been used as an effective drug for the treatment of infections caused by most known species of the herpesvirus family, including herpes simplex and varicella zoster viruses. [[Nucleoside]]s isolated from a Caribbean [[sponge (animal)|sponge]], ''[[Cryptotethya crypta]]'', were the basis for the synthesis of aciclovir.<ref>{{cite book| vauthors = Garrison T |title=Oceanography: An Invitation to Marine Science, 3rd ed.|year=1999|publisher=Wadsworth Publishing Company|location=Belmont, CA|pages=471}}</ref><ref name=bioactive>{{cite journal | vauthors = Sepčić K | s2cid = 84041855 | title = Bioactive Alkylpyridinium Compounds from Marine Sponges | journal = Toxin Reviews | volume = 19 | issue = 2 | pages = 139–160 | year = 2000 | doi = 10.1081/TXR-100100318 }}</ref><ref name=Laport2009>{{cite journal | vauthors = Laport MS, Santos OC, Muricy G | title = Marine sponges: potential sources of new antimicrobial drugs | journal = Current Pharmaceutical Biotechnology | volume = 10 | issue = 1 | pages = 86–105 | date = January 2009 | pmid = 19149592 | doi = 10.2174/138920109787048625 }}</ref> It was codiscovered by Howard Schaeffer following his work with [[Robert Vince (scientist)|Robert Vince]], S. Bittner and S. Gurwara on the adenosine analog acycloadenosine which showed promising antiviral activity.<ref name="Schaffer JMC"/> Later, Schaeffer joined [[Burroughs Wellcome]] and continued the development of aciclovir with [[Pharmacology|pharmacologist]] [[Gertrude B. Elion]].<ref>{{cite journal | vauthors = Elion GB, Furman PA, Fyfe JA, de Miranda P, Beauchamp L, Schaeffer HJ | title = Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 74 | issue = 12 | pages = 5716–5720 | date = December 1977 | pmid = 202961 | pmc = 431864 | doi = 10.1073/pnas.74.12.5716 | doi-access = free | bibcode = 1977PNAS...74.5716E }}</ref> A U.S. patent on aciclovir listing Schaeffer as inventor was issued in 1979.<ref>{{cite patent|country=US|number=4146715 | title = 2-Amido-9-(2-acyloxyethoxymethyl)hypoxanthines | inventor = Schaeffer HJ | assign1 = Burrough Wellcome Co | gdate = 27 March 1979 | postscript = . }}</ref> Vince later invented [[abacavir]], an [[Reverse-transcriptase inhibitor#Nucleoside analog reverse-transcriptase inhibitors (NARTIs or NRTIs)|nRTI]] drug for HIV patients.<ref>{{cite journal | vauthors = Vince R | year = 2008 | title = A brief history of the development of Ziagen | journal = Chemtracts | volume = 21 | pages = 127–134 }}</ref> Elion was awarded the 1988 [[Nobel Prize in Physiology or Medicine|Nobel Prize in Medicine]], partly for the development of aciclovir.<ref>{{cite web |title=The Nobel Prize - Gertrude B. Elion |url=https://www.nobelprize.org/womenwhochangedscience/stories/gertrude-elion}}</ref>

A related [[prodrug]] form, [[valaciclovir]] came into medical use in 1995. It is converted to aciclovir in the body after absorption.<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>

In 2009, acyclovir in combination with hydrocortisone cream, marketed as Xerese, was approved in the United States for the early treatment of recurrent herpes labialis (cold sores) to reduce the likelihood of ulcerative cold sores and to shorten the lesion healing time in adults and children (six years of age and older).<ref>{{cite web | title=Drug Approval Package: Acyclovir and Hydrocortisone NDA #022436 | website=U.S. [[Food and Drug Administration]] (FDA) | date=13 December 2019 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022436_acyclovir_hydrocortisone_toc.cfm | archive-url=https://web.archive.org/web/20191213054239/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022436_acyclovir_hydrocortisone_toc.cfm | archive-date=13 December 2019 | url-status=live | access-date=13 December 2019}} {{PD-notice}}</ref><ref name="Xerese label">{{cite web | title=Xerese- acyclovir and hydrocortisone cream | website=[[DailyMed]] | date=12 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3b6ac164-0f1e-4f36-94a1-1fdb07d710f5 | archive-url=https://web.archive.org/web/20191213054630/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3b6ac164-0f1e-4f36-94a1-1fdb07d710f5 | archive-date=13 December 2019 | url-status=live | access-date=12 December 2019}}</ref>

==Society and culture==

===Names===

It was originally marketed as Zovirax; patents expired in the 1990s and since then it is generic and is marketed under many brand names worldwide.<ref name=Names/>

==Notes==

{{Reflist|group = Note}}

== References ==

{{Reflist}}

== Further reading ==

{{refbegin}}

* {{cite journal | vauthors = Hazra S, Konrad M, Lavie A | title = The sugar ring of the nucleoside is required for productive substrate positioning in the active site of human deoxycytidine kinase (dCK): implications for the development of dCK-activated acyclic guanine analogues | journal = Journal of Medicinal Chemistry | volume = 53 | issue = 15 | pages = 5792–5800 | date = August 2010 | pmid = 20684612 | pmc = 2936711 | doi = 10.1021/jm1005379 }}

* {{cite book | vauthors = Harvey SC | chapter = Drug absorption, action and disposition | pages = 697–702 | veditors = Remington JP, Gennaro AR |title=Remington's Pharmaceutical Sciences |date=1990 |publisher=Mack Pub. Co |location=Easton, Pa. |isbn=978-0-912734-04-0 |edition=18th}}

* {{cite book | vauthors = Huovinen P, Valtonen V | title = Kliininen Farmakologia | veditors = Neuvonen PJ | location = Helsinki | language = fi | publisher = Kandidaattikustannus Oy | date = 1994 | isbn = 951-8951-09-8 }}

* {{cite journal | vauthors = Périgaud C, Gosselin G, Imbach JL | year = 1992 | title = Nucleoside analogues as chemotherapeutic agents: a review | journal = Nucleosides and Nucleotides | volume = 11 | issue = 2–4|pages=903–945 |doi=10.1080/07328319208021748 }}

* {{cite book | vauthors = Rang HP, Dale MM, Ritter JM | title = Pharmacology | publisher = Pearson Professional Ltd | date = 2003 | edition = 5th | isbn = 0-443-07145-4 }}

{{refend}}

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