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| {{drugbox |
| | #REDIRECT[[Acyclovir]] |
| |image = Aciclovir.png
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| |image2 = Aciclovir.jpg
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| |width = 150
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| |IUPAC_name = 2-amino-9-[(2-hydroxyethoxy)methyl]-3,9-dihydro-6H-purin-6-one
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| | synonyms = acycloguanosine
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| |CAS_number = 59277-89-3
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| | ATC_prefix = J05
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| | ATC_suffix = AB01
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| | ATC_supplemental = {{ATC|D06|BB03}} {{ATC|S01|AD03}}
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| | PubChem = 2022
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| | DrugBank = APRD00567
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| | C=8 | H=11 | N=5 | O=3
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| | molecular_weight = 225.21 g/mol
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| | melting_point = 256.5
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| | bioavailability = 10–20% (oral)
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| | protein_bound = 9-33%
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| | metabolism = Viral thymidine kinase
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| | elimination_half-life = 2.2–20 hours
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| | excretion = [[Renal]]
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| | pregnancy_category = B3 <small>([[Australia|Au]])</small>, B <small>([[United States|U.S.]])</small>
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| | legal_status = unscheduled/S4 <small>(Au)</small>, POM <small>([[United Kingdom|UK]])</small>
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| | routes_of_administration = [[intravenous|IV]], oral, topical
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| }}
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| [[Image:Acyclovir pills.jpg|thumb|left|400 mg pills of acyclovir]]
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| {{SI}}
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| ==Overview==
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| '''Aciclovir''' ([[International Nonproprietary Name|INN]]) ([[International Phonetic Alphabet|IPA]]: {{IPA|[eɪˈsaɪklovir]}}) or '''acyclovir''' ([[United States Adopted Name|USAN]], former [[British Approved Name|BAN]]), chemical name '''acycloguanosine''', is a [[guanine analogue]] [[antiviral drug]], marketed under trade names such as ''Zovirax'' and ''Zovir'' ([[GlaxoSmithKline|GSK]]). One of the most commonly-used antiviral drugs, it is primarily used for the treatment of [[herpes simplex virus]] infections, as well as in the treatment of [[Herpes zoster|herpes zoster (shingles)]].
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| Aciclovir was seen as the start of a new era in antiviral therapy, as it is extremely selective and low in [[cytotoxicity]]. [[Pharmacology|Pharmacologist]] [[Gertrude B. Elion]] was awarded the 1988 [[Nobel Prize in Physiology or Medicine|Nobel Prize in Medicine]], partly for the development of aciclovir.
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| ==Pharmacology==
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| ===Mechanism of action===
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| Aciclovir differs from previous [[nucleoside analogues]] in that it contains only a partial [[nucleoside]] structure: the [[pentose|sugar ring]] is replaced by an open-chain structure. It is selectively converted into acyclo-[[guanosine monophosphate]] (acyclo-GMP) 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, acyclo-[[guanosine triphosphate]] (acyclo-GTP), by cellular [[kinase]]s. Acyclo-GTP is a very potent [[Enzyme inhibitor|inhibitor]] of viral [[DNA polymerase]]; it has approximately 100 times greater affinity for viral than cellular polymerase. As a substrate, acyclo-GMP is incorporated into viral DNA, resulting in [[protein biosynthesis#Transcription|chain termination]]. It has also been shown that viral [[enzyme]]s cannot remove acyclo-GMP from the chain, which results in inhibition of further activity of DNA polymerase. Acyclo-GTP is fairly rapidly [[Metabolism|metabolised]] within the cell, possibly by cellular [[phosphatase]]s.
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| In sum, aciclovir can be considered a [[prodrug]]: it is administered in an inactive (or less active form) and is metabolised into a more active species after administration.
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| ===Microbiology===
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| Aciclovir is active against most species in the [[herpesvirus]] family. In descending order of activity:<ref name="OBrien1989">O'Brien JJ, Campoli-Richards DM. Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1989;37(3):233-309. PMID 2653790</ref>
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| *[[Herpes simplex virus]] type I (HSV-1)
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| *Herpes simplex virus type II (HSV-2)
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| *[[Varicella zoster virus]] (VZV)
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| *[[Epstein-Barr virus]] (EBV)
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| *[[Cytomegalovirus]] (CMV)
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| Activity is predominantly against HSV, and to a lesser extent VZV. It is only of limited efficacy against EBV and CMV. It is inactive against latent viruses in [[ganglion|nerve ganglia]].
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| To date, resistance to aciclovir has not been clinically significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase; and mutations to viral thymidine kinase and/or DNA polymerase, altering substrate sensitivity.<ref name="Martindale34">Sweetman S, editor. Martindale: The complete drug reference. 34th ed. London: Pharmaceutical Press; 2004. ISBN 0-85369-550-4</ref>
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| == Pharmacokinetics ==
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| Aciclovir is poorly water soluble and has poor oral [[bioavailability]] (10–20%), hence [[intravenous]] administration is necessary if high concentrations are required. When orally administered, peak plasma concentration occurs after 1–2 hours. Aciclovir has a high distribution rate, only 30% is protein-bound in plasma. The [[elimination half-life]] of aciclovir is approximately 3 hours. It is renally excreted, partly by [[Renal physiology#Glomerular filtration|glomerular filtration]] and partly by [[Renal physiology#Tubular secretion|tubular secretion]].
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| ==Clinical use==
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| === Indications ===
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| Aciclovir is indicated 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</ref>
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| * Genital [[herpes simplex]] (treatment and [[prophylaxis]])
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| * Herpes simplex labialis ([[cold sores]])
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| * [[Herpes zoster]] (shingles)
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| * Acute [[chickenpox]] in immunocompromised patients
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| * [[Herpes simplex encephalitis]]
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| * Acute mucocutaneous HSV infections in immunocompromised patients
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| * Herpes simplex [[keratitis]] (ocular herpes)
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| * Herpes simplex [[blepharitis]] (not to be mistaken with ocular herpes)
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| * Bell's Palsy
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| It has been claimed that the evidence for the effectiveness of topically applied cream for recurrent labial outbreaks is weak.<ref>{{cite journal | author=Graham Worrall | title=Evidence for efficacy of topical acyclovir in recurrent herpes labialis is weak | journal=BMJ | year=1996 | month=6 Jul | volume=313 | pages=46 | url=http://www.bmj.com/cgi/content/full/313/7048/46/a}}- Letter</ref>
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| Likewise oral therapy for episodes is inappropriate for most non-immunocompromised patients, whilst there is evidence for oral prophylactic role in preventing recurrences.<ref>{{cite journal | author=Graham Worrall | title=Acyclovir in recurrent herpes labialis | journal=BMJ | year=1996 | month=6 Jan | volume=312 | pages=6 | url=http://www.bmj.com/cgi/content/full/312/7022/6}} - Editorial</ref>
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| === Dosage forms ===
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| Aciclovir is commonly marketed as tablets (200 mg, 400 mg and 800 mg), topical cream (5%), intravenous injection (25 mg/mL) and ophthalmic ointment (3%). Cream preparations are used primarily for labial herpes simplex. The intravenous injection is used when high concentrations of aciclovir are required. The ophthalmic ointment preparation is only used for herpes simplex keratitis .
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| == Adverse effects ==
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| ===Systemic therapy===
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| Common [[adverse drug reaction]]s (≥1% of patients) associated with systemic aciclovir therapy (oral or IV) include: nausea, vomiting, diarrhea and/or 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, rash and/or 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]] and/or [[anaphylaxis]].<ref name="AMH2006" />
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| Additional common adverse effects, when aciclovir is administered IV, include [[encephalopathy]] (1% of patients) and injection site reactions. The injection formulation is [[alkaline]] ([[pH]] 11), and [[extravasation]] may cause local tissue pain and irritation.<ref name="AMH2006" /> Renal impairment has been reported when aciclovir is given in large, fast doses intravenously, due to the crystallisation of aciclovir in the kidneys.
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| ===Topical therapy===
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| Aciclovir topical cream is commonly associated (≥1% of patients) with: dry or flaking skin and/or transient stinging/burning sensations. Infrequent adverse effects include [[erythema]] and/or itch.<ref name="AMH2006" />
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| 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]] and/or allergic reactions.<ref name="AMH2006" />
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| ===Toxicity===
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| 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 [[teratogen]]ic nor [[carcinogen]]ic effects. The acute toxicity ([[LD50|LD<sub>50</sub>]]) of aciclovir when given orally is greater than 1 g/kg, due to the low oral bioavailability. Single cases have been reported, where extremely high (up to 80 mg/kg) doses have been accidentally given intravenously without causing any major adverse effects.
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| == Footnotes ==
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| <div class="references-small">{{reflist|2}}</div>
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| == Further reading ==
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| * Harvey Stewart C. in Remington’s Pharmaceutical Sciences 18th edition: (ed. Gennard, Alfonso R.) Mack Publishing Company, 1990. ISBN 0-912734-04-3.
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| * Huovinen P., Valtonen V. in Kliininen Farmakologia (ed. Neuvonen et al.). Kandidaattikustannus Oy, 1994. ISBN 951-8951-09-8.
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| * Périgaud C., Gosselin G., Imbach J. -L.: Nucleoside analogues as chemotherapeutic agents: a review. Nucleosides and nucleotides 1992; 11(2-4)
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| * Rang H.P., Dale M.M., Ritter J.M.: Pharmacology, 3<sup>rd</sup> edition. Pearson Professional Ltd, 1995. 2003 (5th) edition ISBN 0-443-07145-4; 2001 (4th) edition ISBN 0-443-06574-8; 1990 edition ISBN 0-443-03407-9.
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| {{Antibiotics and chemotherapeutics for dermatological use}}
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| {{Antivirals}}
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| [[Category:Purines]]
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| [[Category:Antivirals]]
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