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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|last=Razonable|first=RR|title=Antiviral drugs for viruses other than human immunodeficiency virus|journal=Mayo Clinic Proceedings|date=October 2011|volume=86|issue=10|pages=1009–26|pmid=21964179|doi=10.4065/mcp.2011.0309|pmc=3184032|df=}}</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=182–5 |date=July 1982 |pmid=6285711 |doi= 10.1016/0002-9343(82)90087-0|url=}}</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=1067–71|date=June 1988 |pmid=3376977 |doi= 10.1016/0002-9343(88)90313-0|url=}}</ref>
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|last=Razonable|first=RR|title=Antiviral drugs for viruses other than human immunodeficiency virus|journal=Mayo Clinic Proceedings|date=October 2011|volume=86|issue=10|pages=1009–26|pmid=21964179|doi=10.4065/mcp.2011.0309|pmc=3184032|df=}}</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=182–5 |date=July 1982 |pmid=6285711 |doi= 10.1016/0002-9343(82)90087-0|url=}}</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=1067–71|date=June 1988 |pmid=3376977 |doi= 10.1016/0002-9343(88)90313-0|url=}}</ref>


The aciclovir metabolite [[9-carboxymethoxymethylguanine]] (9-CMMG) has been shown to play a role in neurological adverse events, particularly in people with reduced kidney function.<ref>{{cite journal |last1=Berry |first1=L. |last2=Venkatesan |first2=P. |title=Aciclovir-induced neurotoxicity: Utility of CSF and serum CMMG levels in diagnosis |journal=Journal of Clinical Virology |date=December 2014 |volume=61 |issue=4 |pages=608–610 |doi=10.1016/j.jcv.2014.09.001 |pmid=25440915}}</ref>
The aciclovir can cause neurological adverse events, particularly in people with reduced kidney function.<ref>{{cite journal |last1=Chowdhury |first1=MA |last2=Derar |first2=N |last3=Hasan |first3=S |last4=Hinch |first4=B |last5=Ratnam |first5=S |last6=Assaly |first6=R |title=Acyclovir-Induced Neurotoxicity: A Case Report and Review of Literature. |journal=American journal of therapeutics |date=2016 |volume=23 |issue=3 |pages=e941-3 |doi=10.1097/MJT.0000000000000093 |pmid=24942005}}</ref>


===Topical therapy===
===Topical therapy===

Revision as of 07:20, 30 May 2019

Aciclovir
Clinical data
Pronunciation/eɪˈsaɪkloʊvɪər/
Trade namesZovirax, others[1]
Other namesacycloguanosine, acyclovir (BAN UK), acyclovir (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa681045
License data
Pregnancy
category
  • AU: B3
Routes of
administration		Intravenous, by mouth, topical (including eye ointment)
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) for tablet and injection. Unscheduled for cream form under 10 g.
  • CA: ℞-only
  • UK: POM (Prescription only) for tablet and injection. GSL (OTC) for cream form under 2 g.
  • US: ℞-only
Pharmacokinetic data
Bioavailability15–20% (by mouth)[2]
Protein binding9–33%[2]
MetabolismLiver
Elimination half-life2–4 hours
ExcretionKidney (62–90% as unchanged drug)
Identifiers
  • 2-Amino-1,9-dihydro-9-((2-hydroxyethoxy)methyl)-3H-purin-6-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.056.059 Edit this at Wikidata
Chemical and physical data
FormulaC8H11N5O3
Molar mass225.208 g·mol−1
3D model (JSmol)
Melting point256.5 °C (493.7 °F)
  • O=C2/N=C(\Nc1n(cnc12)COCCO)N
  • InChI=1S/C8H11N5O3/c9-8-11-6-5(7(15)12-8)10-3-13(6)4-16-2-1-14/h3,14H,1-2,4H2,(H3,9,11,12,15) checkY
  • Key:MKUXAQIIEYXACX-UHFFFAOYSA-N checkY
  (verify)

Aciclovir (ACV), also known as acyclovir, is an antiviral medication.[3] It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles.[4] Other uses include prevention of cytomegalovirus infections following transplant and severe complications of Epstein-Barr virus infection.[4][5] It can be taken by mouth, applied as a cream, or injected.[4]

Common side effects include nausea and diarrhea.[4] Potentially serious side effects include kidney problems and low platelets.[4] Greater care is recommended in those with poor liver or kidney function.[4] It is generally considered safe for use in pregnancy with no harm having been observed.[4][6] It appears to be safe during breastfeeding.[7][8] Aciclovir is a nucleoside analogue that is similar to guanosine.[4] It works by decreasing the production of the virus's DNA.[4]

Aciclovir was patented in 1974 and approved for medical use in 1981.[9] It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[10] It is available as a generic medication and is marketed under many brand names worldwide.[1] The wholesale cost as of 2014 to 2016 was between US$0.03 and US$0.12 for a typical dose by mouth.[11][12] The cost of a typical course of treatment in the United States is less than US$25.[7] In 2016 it was the 195th most prescribed medication in the United States with more than 3 million prescriptions.[13]

Medical use

400 mg pills of aciclovir

Aciclovir is used for the treatment of herpes simplex virus and varicella zoster virus infections, including:[2][14][15]

Its effectiveness in treating Epstein-Barr virus (EBV) infections is less clear.[4] It has not been found to be useful for infectious mononucleosis due to EBV.[17]

Aciclovir taken by mouth does not appear to decrease the risk of pain after shingles.[18] In those with herpes of the eye, aciclovir may be more effective and safer than idoxuridine.[19] It is not clear if aciclovir eye drops are more effective than brivudine eye drops.[19]

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 herpetic encephalitis. It is also effective in systemic or traumatic herpes infections, eczema herpeticum and herpes simplex 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.[20] 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.[21] 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 anti-retroviral therapy (ART). This finding emphasizes the importance of testing simple, inexpensive non-ART strategies, such as aciclovir and cotrimoxazole, in people with HIV.[22]

Pregnancy

Classified as a Category B Drug,[23] the CDC and others have declared that during severe recurrent or first episodes of genital herpes, aciclovir may be used.[24] For severe HSV infections (especially disseminated HSV), IV aciclovir may also be used.[25] 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.[26] Studies in rats in which they were given the equivalent to 63 times the standard steady-state humans concentrations of the drug[Note 1] on day 10 of gestation showed head and tail anomalies.[26]

Aciclovir is recommended by the CDC for treatment of varicella during pregnancy, especially during the second and third trimesters[27]

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 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.[23][28]

Adverse effects

Systemic therapy

Common adverse drug reactions (≥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, hallucinations have been reported. Infrequent adverse effects (0.1–1% of patients) include agitation, 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, fatigue, hepatitis, Stevens–Johnson syndrome, toxic epidermal necrolysis, thrombotic thrombocytopenic purpura and anaphylaxis.[14]

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.[29][30][31]

The aciclovir can cause neurological adverse events, particularly in people with reduced kidney function.[32]

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.[14] 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.[14]

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.[33]

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.[23]

Interferon: Synergistic effects when administered with aciclovir and caution should be taken when administering aciclovir to patients receiving IV interferon.[34]

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.[35]

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.[36]

Mechanism of action

Structures of guanosine and aciclovir compared

Aciclovir is converted by viral thymidine kinase to aciclovir monophosphate, which is then converted by host cell kinases to aciclovir triphosphate (ACV-TP).[26] ACV-TP, in turn, competitively inhibits and inactivates HSV-specified DNA polymerases preventing further viral DNA synthesis without affecting the normal cellular processes.[26][37][38]

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 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.[39][40]

Microbiology

Varicella zoster virus-produced plaques in monolayers of MRC5 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:[41][42]

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. Aciclovir has a high distribution rate; protein binding is reported to range from 9 to 33%.[43] The elimination half-life (t1/2) of aciclovir depends according to age group; neonates have a t1/2 of 4 hours, children 1–12 years have a t1/2 of 2–3 hours whereas adults have a t1/2 of 3 hours.[2]

History

Aciclovir was seen as the start of a new era in antiviral therapy, as it is extremely selective and low in cytotoxicity.[3] 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. Nucleosides isolated from a Caribbean sponge, Cryptotethya crypta, were the basis for the synthesis of aciclovir.[44][45][46] It was codiscovered by Howard Schaeffer following his work with Robert Vince, S. Bittner and S. Gurwara on the adenosine analog acycloadenosine which showed promising antiviral activity.[47] Later, Schaeffer joined Burroughs Wellcome and continued the development of aciclovir with pharmacologist Gertrude B. Elion.[48] A U.S. patent on aciclovir listing Schaeffer as inventor was issued in 1979.[49]

Vince later went on to invent abacavir, an nRTI drug for HIV patients.[50] Elion was awarded the 1988 Nobel Prize in Medicine, partly for the development of aciclovir. Richard Whitley, a University of Alabama at Birmingham researcher, was the first to successfully use the drug in humans.[citation needed]

Society and culture

Names

Aciclovir is the INN and BAN while acyclovir is the USAN and former BAN.

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.[1]

Cost

The wholesale cost for a 400 mg tablet in March 2016 was between US$0.03 and US$0.12 per dose.[11][12]

Notes

  1. ^ Subject to the same conditions as before

References

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  3. ^ a b de Clercq, Erik; Field, Hugh J (5 October 2005). "Antiviral prodrugs – the development of successful prodrug strategies for antiviral chemotherapy". British Journal of Pharmacology. Vol. 147, no. 1. Wiley-Blackwell (published January 2006). pp. 1–11. doi:10.1038/sj.bjp.0706446. PMC 1615839. PMID 16284630.
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  5. ^ Rafailidis PI, Mavros MN, Kapaskelis A, Falagas ME (2010). "Antiviral treatment for severe EBV infections in apparently immunocompetent patients". Journal of Clinical Virology : The Official Publication of the Pan American Society for Clinical Virology. 49 (3): 151–7. doi:10.1016/j.jcv.2010.07.008. PMID 20739216.
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  30. ^ Brigden D, Rosling AE, Woods NC (July 1982). "Renal function after acyclovir intravenous injection". The American Journal of Medicine. 73 (1A): 182–5. doi:10.1016/0002-9343(82)90087-0. PMID 6285711.
  31. ^ Sawyer MH, Webb DE, Balow JE, Straus SE (June 1988). "Acyclovir-induced renal failure. Clinical course and histology". The American Journal of Medicine. 84 (6): 1067–71. doi:10.1016/0002-9343(88)90313-0. PMID 3376977.
  32. ^ Chowdhury, MA; Derar, N; Hasan, S; Hinch, B; Ratnam, S; Assaly, R (2016). "Acyclovir-Induced Neurotoxicity: A Case Report and Review of Literature". American journal of therapeutics. 23 (3): e941-3. doi:10.1097/MJT.0000000000000093. PMID 24942005.
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Further reading

Retrieved from "https://en.wikipedia.org/w/index.php?title=Aciclovir&oldid=899466982"