Aciclovir

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Aciclovir
Aciclovir2DACS.svg
Aciclovir3Dan.gif
Systematic (IUPAC) name
2-Amino-1,9-dihydro-9-((2-hydroxyethoxy)methyl)-6H-purin-6-one
Clinical data
Trade names Zovirax
AHFS/Drugs.com monograph
MedlinePlus a681045
Licence data US FDA:link
Pregnancy cat. B3 (AU) B (US)
Legal status unscheduled (CREAM FORM under 10g ) (AU) -only (CA) GSL (CREAM FORM under 2g ) (UK) -only (US)
Routes Intravenous, oral, topical (including eye ointment)
Pharmacokinetic data
Bioavailability 15–20% (oral)[1]
Protein binding 9–33%[1]
Metabolism Hepatic
Half-life 2-4 hours
Excretion Renal (62-90% as unchanged drug)
Identifiers
CAS number 59277-89-3 YesY
ATC code J05AB01 D06BB03 S01AD03
PubChem CID 2022
DrugBank DB00787
ChemSpider 1945 YesY
UNII X4HES1O11F YesY
KEGG D00222 YesY
ChEBI CHEBI:2453 YesY
ChEMBL CHEMBL184 YesY
Synonyms acycloguanosine
PDB ligand ID AC2 (PDBe, RCSB PDB)
Chemical data
Formula C8H11N5O3 
Mol. mass 225.21 g/mol
Physical data
Melt. point 256.5 °C (494 °F)
 YesY (what is this?)  (verify)

Aciclovir (INN, BAN. Brand names: Cyclovir, Herpex, Acivir, Acivirax, Zovirax, Zoral, Xovir and Imavir) /ˈsklɵvɪər/ or acyclovir (USAN, former BAN), chemical name acycloguanosine, abbreviated as ACV,[2] is a guanosine analogue antiviral drug. It is one of the most commonly used antiviral drugs, that is primarily used for the treatment of herpes simplex virus infections, as well as in the treatment of varicella zoster (chickenpox) and herpes zoster (shingles).

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[3]

Medical use[edit]

400 mg pills of aciclovir

Aciclovir is indicated for the treatment of HSV and VZV infections, including:[1][4][5]

It has been claimed that the evidence for the effectiveness of topically applied cream for recurrent labial outbreaks is weak.[7] An earlier review of scientific literature showed there is some effect in reducing the number and duration of lesions if aciclovir is applied at an early stage of an outbreak.[8] 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.[9]

A systematic review found that in the treatment of individuals suffering from herpes of the eye, aciclovir was found to be significantly more effective than idoxuridine or vidarabine in relative number of successfully healed eyes.[10]

Pregnancy[edit]

Classified as a Category B Drug,[11] the CDC and others have declared that during severe recurrent or first episodes of genital herpes, aciclovir may be used.[12] For severe HSV infections (especially disseminated HSV), IV aciclovir may also be used.[13] 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.[14] 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.[14]

Aciclovir is recommended by the CDC for treatment of Varicella during pregnancy, especially during the second and third trimesters[15]

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 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.[16]

Adverse effects[edit]

Systemic therapy[edit]

Common adverse drug reactions (≥1% of patients) associated with systemic aciclovir therapy (oral or IV) include: nausea, vomiting, diarrhoea, 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.[4]

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.[17][18][19]

Topical therapy[edit]

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.[4] 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.[4]

Drug Interactions[edit]

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 is not been clinically established and more studies need to be done to evaluate the true potential of this synergy.[20]

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.[11]

Interferon: Synergistic effects when administered with aciclovir and caution should be taken when administering aciclovir to patients recieiving IV interferon.[21]

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.[22]

Detection in biological fluids[edit]

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.[23]

Mechanism of action[edit]

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).[14] ACV-TP, in turn, competitively inhibits and inactivates DNA polymerases and incorporates itself into viral DNA chain.[14][24][25]

Microbiology[edit]

Aciclovir is active against most species in the herpesvirus family. In descending order of activity:[26][27]

Resistance[edit]

Resistance to aciclovir is rare, but is more common in patients 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.[28]

Pharmacokinetics[edit]

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%.[29] 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.[1]

History[edit]

Aciclovir was seen as the start of a new era in antiviral therapy,[2] as it is extremely selective and low in cytotoxicity. Nucleosides isolated from a Caribbean sponge, Cryptotethya crypta, were the basis for the synthesis of aciclovir.[30][31][32] It was codiscovered by Howard Schaffer following his work with Robert Vince, S. Bittner and S. Gurwara on the adenosine analog acycloadenosine which showed promising antiviral activity.[33] Later, Schaffer joined Burroughs Wellcome and continued the development of aciclovir with pharmacologist Gertrude B. Elion.[34] A U.S. patent on aciclovir listing Schaffer as inventor was issued in 1979.[35]

Vince later went on to invent abacavir, an nRTI drug for HIV patients.[36] Elion was awarded the 1988 Nobel Prize in Medicine, partly for the development of aciclovir. Richard Whitley, a University of Alabama at Birmingham researcher and pioneer in antiviral therapy, was the first to successfully use the drug in humans.

Synthesis[edit]

Acyclovir synthesis.[37]

See also[edit]

Notes[edit]

  1. ^ Subject to the same conditions as before

References[edit]

  1. ^ a b c d "Zovirax (acyclovir) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 5 February 2014. 
  2. ^ 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 147 (1) (Wiley-Blackwell, published January 2006). pp. 1–11. doi:10.1038/sj.bjp.0706446. PMC 1615839. PMID 16284630. 
  3. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  4. ^ a b c d Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.  edit
  5. ^ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.  edit
  6. ^ Elad S, Zadik Y, Hewson I, et al. (August 2010). "A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea". Support Care Cancer 18 (8): 993–1006. doi:10.1007/s00520-010-0900-3. PMID 20544224. 
  7. ^ Worrall, G (July 1996). "Evidence for efficacy of topical acyclovir in recurrent herpes labialis is weak." (PDF). BMJ (Clinical research ed.) 313 (7048): 46. doi:10.1136/bmj.313.7048.46a. PMC 2351426. PMID 8664786. 
  8. ^ Graham Worrall (6 Jan 1996). "Acyclovir in recurrent herpes labialis". BMJ 312 (7022): 6. doi:10.1136/bmj.312.7022.6. PMC 2349724. PMID 8555890.  – Editorial
  9. ^ Mascolinli, M; Kort, R (June 2010). "5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention: summary of key research and implications for policy and practice - biomedical prevention" (PDF). Journal of the International AIDS Society. 13 Suppl 1 (Suppl 1): S4. doi:10.1186/1758-2652-13-S1-S4. PMC 2880255. PMID 20519025. 
  10. ^ Wilhelmus KR (2010). "Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis". Cochrane Database Syst Rev 12: CD002898. doi:10.1002/14651858.CD002898.pub4. PMID 21154352. 
  11. ^ a b GlaxoSmithKline. Zovirax® (acyclovir) capsules, tablets, and suspension prescribing information. Research Triangle Park, NC; 2005 Jun
  12. ^ Drugs for non-HIV viral infections. Treat Guidel Med Lett. 2005; 3:23-32. [PubMed 15767977]
  13. ^ Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recomm Rep. 2004; 53(RR-15):1-112. [Fulltext MMWR]
  14. ^ a b c d "PRODUCT INFORMATION NAME OF THE DRUG OZVIR TABLETS" (PDF). TGA eBusiness Services. Ranbaxy Australia Pty Ltd. 26 August 2011. Retrieved 6 February 2014. 
  15. ^ Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. 9th ed. Public Health Foundation; 2006 Jan:171-92
  16. ^ Gartner LM, Morton J, Lawrence RA, et al, "Breastfeeding and the Use of Human Milk," Pediatrics, 2005, 115(2):496-506
  17. ^ Razonable, RR (October 2011). "Antiviral drugs for viruses other than human immunodeficiency virus" (PDF). Mayo Clinic proceedings. Mayo Clinic 86 (10): 1009–26. doi:10.4065/mcp.2011.0309. PMC 3184032. PMID 21964179. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ Pottage JC, Kessler HA, Goodrich JM et al. In vitro activity of ketoconazole against herpes simplex virus. Antimicrob Agents Chemother. 1986; 30:215-9. [IDIS 220405] [PubMed 3021048][Free Fulltext PMC]
  21. ^ GlaxoSmithKline. Zovirax® (acyclovir sodium) for injection prescribing information. Research Triangle Park, NC; 2003 Nov
  22. ^ Bach MC. Possible drug interaction during therapy with azidothymidine and acyclovir for AIDS. N Engl J Med. 1987; 316:547. [IDIS 225771] [PubMed 3468354]
  23. ^ Baselt, RC (2008). Disposition of toxic drugs and chemicals in man (8th ed. ed.). Foster City, CA: Biomedical Publications. pp. 29–31. ISBN 9780962652370. 
  24. ^ "Acyclovir (acyclovir) Capsule Acyclovir (acyclovir) Tablet [Genpharm Inc.]". DailyMed. Genpharm Inc. November 2006. Retrieved 5 February 2014. 
  25. ^ "Aciclovir Tablets BP 400mg - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Actavis UK Ltd. 20 August 2012. Retrieved 5 February 2014. 
  26. ^ O'Brien, JJ; Campoli-Richards, DM (1989). "Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy". Drugs 37 (3): 233–309. PMID 2653790. 
  27. ^ Wagstaff, AJ; Faulds, D; Goa, KL (January 1994). "Aciclovir. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic efficacy.". Drugs 47 (1): 153–205. doi:10.2165/00003495-199447010-00009. PMID 7510619. 
  28. ^ Sweetman, S, ed. (7 August 2013). "Aciclovir". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 6 February 2014. 
  29. ^ Aciclovir Tablets BP 400mg - Summary of Product Characteristics (SPC) - (eMC)
  30. ^ Garrison, Tom (1999). Oceanography: An Invitation to Marine Science, 3rd ed. Belmont, CA: Wadsworth Publishing Company. p. 471. 
  31. ^ Sepčić, K. (2000). "Bioactive Alkylpyridinium Compounds from Marine Sponges". Toxin Reviews 19 (2): 139–160. doi:10.1081/TXR-100100318.  edit
  32. ^ Laport, M. S.; Santos, O. C.; Muricy, G. (2009). "Marine sponges: Potential sources of new antimicrobial drugs". Current pharmaceutical biotechnology 10 (1): 86–105. PMID 19149592.  edit
  33. ^ Schaffer, Howard; Robert Vince; S. Bittner; S. Gurwara (1971). "Novel substrate of adenosine deaminase". Journal of Medicinal Chemistry 14 (4): 367–369. doi:10.1021/jm00286a024. PMID 5553754. 
  34. ^ Elion, Gertrude; Furman, Fyfe, Miranda, Beauchamp and Schaffer (1977). "Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl)guanine". Proc Natl Acad Sci USA 74 (12): 5716–5720. doi:10.1073/pnas.74.12.5716. PMC 431864. PMID 202961. 
  35. ^ US 4146715 
  36. ^ Vince, R. "A brief history of the development of Ziagen" Chemtracts 2008, 21, 127–134.
  37. ^ http://drugsynthesis.blogspot.co.uk/2011/11/laboratory-synthesis-of-acyclovir.html

Further reading[edit]

External links[edit]