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


Aciclovir is indicated for the treatment of HSV and VZV infections, including:<ref name =MSR/><ref name=AMH>{{cite isbn|9780980579093}}</ref><ref name = BNF>{{cite isbn|9780857110848}}</ref>
Aciclovir is used for the treatment of [[herpes simplex virus]] and [[varicella zoster virus]] infections, including:<ref name =MSR/><ref name=AMH>{{cite isbn|9780980579093}}</ref><ref name = BNF>{{cite isbn|9780857110848}}</ref>
* Genital [[herpes simplex]] (treatment and [[prophylaxis|prevention]])
* Genital [[herpes simplex]] (treatment and [[prophylaxis|prevention]])
* Herpes simplex labialis ([[cold sores]])
* Herpes simplex labialis ([[cold sores]])
Line 97: Line 97:
* Prophylaxis against herpes viruses in immunocompromised patients (such as patients undergoing cancer chemotherapy)<ref name="Cancer">{{cite journal |author=Elad S, Zadik Y, Hewson I, et al. |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 }}</ref>
* Prophylaxis against herpes viruses in immunocompromised patients (such as patients undergoing cancer chemotherapy)<ref name="Cancer">{{cite journal |author=Elad S, Zadik Y, Hewson I, et al. |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 }}</ref>


⚫
Oral aciclovir; however, does not appear to decrease the risk of pain after shingles.<ref>{{cite journal|last1=Chen|first1=N|last2=Li|first2=Q|last3=Yang|first3=J|last4=Zhou|first4=M|last5=Zhou|first5=D|last6=He|first6=L|title=Antiviral treatment for preventing postherpetic neuralgia.|journal=The Cochrane database of systematic reviews|date=2014 Feb 6|volume=2|pages=CD006866|pmid=24500927}}</ref> In those with herpes of the eye, aciclovir was found to be more effective than [[idoxuridine]] or [[vidarabine]] in relative number of successfully healed eyes.<ref name="Wilhelmus">{{cite journal |author= Wilhelmus KR |title= Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis |journal=Cochrane Database Syst Rev|volume=12 |pages= CD002898 |date=2010 |pmid= 21154352|doi= 10.1002/14651858.CD002898.pub4}}</ref>
It has been claimed that the evidence for the effectiveness of topically applied cream for recurrent labial outbreaks is weak.<ref>{{cite journal|last=Worrall|first=G|title=Evidence for efficacy of topical acyclovir in recurrent herpes labialis is weak.|journal=BMJ (Clinical research ed.)|date=July 1996|volume=313|issue=7048|pages=46|doi=10.1136/bmj.313.7048.46a|pmid=8664786|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2351426/pdf/bmj00549-0050b.pdf|format=PDF|pmc=2351426}}</ref>
⚫
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.<ref>{{cite journal | author=Graham Worrall | title=Acyclovir in recurrent herpes labialis|journal=BMJ | date=6 Jan 1996 | volume=312 | page=6 | url=http://www.bmj.com/cgi/content/full/312/7022/6 | pmid=8555890 | issue=7022|pmc=2349724 | doi=10.1136/bmj.312.7022.6}} – Editorial</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|last=Mascolinli|first=M|author2=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|date=June 2010|volume=13 Suppl 1|pages=S4|pmid=20519025|doi=10.1186/1758-2652-13-S1-S4|pmc=2880255|issue=Suppl 1|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880255/pdf/1758-2652-13-S1-S4.pdf|format=PDF}}</ref>


⚫
The evidence for the effectiveness of topically applied cream for recurrent labial outbreaks is weak.<ref>{{cite journal|last=Worrall|first=G|title=Evidence for efficacy of topical acyclovir in recurrent herpes labialis is weak.|journal=BMJ (Clinical research ed.)|date=July 1996|volume=313|issue=7048|pages=46|doi=10.1136/bmj.313.7048.46a|pmid=8664786|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2351426/pdf/bmj00549-0050b.pdf|format=PDF|pmc=2351426}}</ref> 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.<ref>{{cite journal | author=Graham Worrall | title=Acyclovir in recurrent herpes labialis|journal=BMJ | date=6 Jan 1996 | volume=312 | page=6 | url=http://www.bmj.com/cgi/content/full/312/7022/6 | pmid=8555890 | issue=7022|pmc=2349724 | doi=10.1136/bmj.312.7022.6}} – Editorial</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|last=Mascolinli|first=M|author2=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|date=June 2010|volume=13 Suppl 1|pages=S4|pmid=20519025|doi=10.1186/1758-2652-13-S1-S4|pmc=2880255|issue=Suppl 1|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2880255/pdf/1758-2652-13-S1-S4.pdf|format=PDF}}</ref>
⚫
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.<ref name="Wilhelmus">{{cite journal |author= Wilhelmus KR |title= Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis |journal=Cochrane Database Syst Rev|volume=12 |pages= CD002898 |date=2010 |pmid= 21154352|doi= 10.1002/14651858.CD002898.pub4}}</ref>

A systematic review found that treatment with oral aciclovir in the acute fase of the herpetic rash of shingles did not reduce the incidence of nerve pain ([[postherpetic neuralgia]]) at 4 and 6 month. The results of the review were limited to oral antiviral agents (aciclovir and famciclovir), and immunocompetent patients with herpes zoster. Evidence of efficacy on outcomes, such as pain severity and quality of life, could not be shown.<ref name="cochrane PHN">{{cite web|last1=Chen|first1=N|title=Antiviral treatment for preventing nerve pain after shingles (postherpetic neuralgia) 6 February 2014|url=http://summaries.cochrane.org/CD006866/antiviral-treatment-for-preventing-nerve-pain-after-shingles-postherpetic-neuralgia|publisher=Cochrane summaries}}</ref>


===Pregnancy===
===Pregnancy===

Revision as of 00:11, 21 July 2014

Aciclovir
Clinical data
Trade namesZovirax
Other namesacycloguanosine
AHFS/Drugs.comMonograph
MedlinePlusa681045
License data
Pregnancy
category
  • AU: B3
Routes of
administration		Intravenous, oral, topical (including eye ointment)
ATC code
Legal status
Legal status
  • AU: unscheduled (CREAM FORM under 10g )
  • CA: ℞-only
  • UK: GSL (CREAM FORM under 2g )
  • US: ℞-only
Pharmacokinetic data
Bioavailability15–20% (oral)[1]
Protein binding9–33%[1]
MetabolismHepatic
Elimination half-life2-4 hours
ExcretionRenal (62-90% as unchanged drug)
Identifiers
  • 2-Amino-1,9-dihydro-9-((2-hydroxyethoxy)methyl)-6H-purin-6-one
CAS Number
PubChem CID
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 mass225.21 g/mol 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 (INN, BAN. Brand names: Cyclovir, Herpex, Acivir, Acivirax, Zovirax, Zoral, Xovir and Imavir) /eɪˈsaɪkl[invalid input: 'ɵ']vɪər/ 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

400 mg pills of aciclovir

Aciclovir is used for the treatment of herpes simplex virus and varicella zoster virus infections, including:[1][4][5]

Oral aciclovir; however, does not appear to decrease the risk of pain after shingles.[7] In those with herpes of the eye, aciclovir was found to be more effective than idoxuridine or vidarabine in relative number of successfully healed eyes.[8]

The evidence for the effectiveness of topically applied cream for recurrent labial outbreaks is weak.[9] 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.[10] 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.[11]

Pregnancy

Classified as a Category B Drug,[12] the CDC and others have declared that during severe recurrent or first episodes of genital herpes, aciclovir may be used.[13] For severe HSV infections (especially disseminated HSV), IV aciclovir may also be used.[14] 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.[15] 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.[15]

Aciclovir is recommended by the CDC for treatment of Varicella during pregnancy, especially during the second and third trimesters[16]

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.[17]

Adverse effects

Systemic therapy

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.[18][19][20]

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.[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

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.[21]

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.[12]

Interferon: Synergistic effects when administered with aciclovir and caution should be taken when administering aciclovir to patients recieiving IV interferon.[22]

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.[23]

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.[24]

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).[15] ACV-TP, in turn, competitively inhibits and inactivates DNA polymerases and incorporates itself into viral DNA chain.[15][25][26]

Microbiology

Aciclovir is active against most species in the herpesvirus family. In descending order of activity:[27][28]

Resistance

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.[29]

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%.[30] 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

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.[31][32][33] 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.[34] Later, Schaffer joined Burroughs Wellcome and continued the development of aciclovir with pharmacologist Gertrude B. Elion.[35] A U.S. patent on aciclovir listing Schaffer as inventor was issued in 1979.[36]

Vince later went on to invent abacavir, an nRTI drug for HIV patients.[37] 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

Acyclovir synthesis.[38]

See also

Notes

  1. ^ Subject to the same conditions as before

References

  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. Vol. 147, no. 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" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  4. ^ a b c d Template:Cite isbn
  5. ^ Template:Cite isbn
  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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  7. ^ Chen, N; Li, Q; Yang, J; Zhou, M; Zhou, D; He, L (2014 Feb 6). "Antiviral treatment for preventing postherpetic neuralgia". The Cochrane database of systematic reviews. 2: CD006866. PMID 24500927. {{cite journal}}: Check date values in: |date= (help)
  8. ^ 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.
  9. ^ 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.
  10. ^ 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
  11. ^ 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  12. ^ a b GlaxoSmithKline. Zovirax® (acyclovir) capsules, tablets, and suspension prescribing information. Research Triangle Park, NC; 2005 Jun
  13. ^ Drugs for non-HIV viral infections. Treat Guidel Med Lett. 2005; 3:23-32. [PubMed 15767977]
  14. ^ 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]
  15. ^ 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.
  16. ^ Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. 9th ed. Public Health Foundation; 2006 Jan:171-92
  17. ^ Gartner LM, Morton J, Lawrence RA, et al, "Breastfeeding and the Use of Human Milk," Pediatrics, 2005, 115(2):496-506
  18. ^ 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.
  19. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ 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]
  22. ^ GlaxoSmithKline. Zovirax® (acyclovir sodium) for injection prescribing information. Research Triangle Park, NC; 2003 Nov
  23. ^ Bach MC. Possible drug interaction during therapy with azidothymidine and acyclovir for AIDS. N Engl J Med. 1987; 316:547. [IDIS 225771] [PubMed 3468354]
  24. ^ Baselt, RC (2008). Disposition of toxic drugs and chemicals in man (8th ed. ed.). Foster City, CA: Biomedical Publications. pp. 29–31. ISBN 9780962652370. {{cite book}}: |edition= has extra text (help)
  25. ^ "Acyclovir (acyclovir) Capsule Acyclovir (acyclovir) Tablet [Genpharm Inc.]". DailyMed. Genpharm Inc. November 2006. Retrieved 5 February 2014.
  26. ^ "Aciclovir Tablets BP 400mg - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Actavis UK Ltd. 20 August 2012. Retrieved 5 February 2014.
  27. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ^ 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.
  29. ^ Sweetman, S, ed. (7 August 2013). "Aciclovir". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 6 February 2014.
  30. ^ Aciclovir Tablets BP 400mg - Summary of Product Characteristics (SPC) - (eMC)
  31. ^ Garrison, Tom (1999). Oceanography: An Invitation to Marine Science, 3rd ed. Belmont, CA: Wadsworth Publishing Company. p. 471.
  32. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1081/TXR-100100318, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1081/TXR-100100318 instead.
  33. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19149592, please use {{cite journal}} with |pmid=19149592 instead.
  34. ^ 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.
  35. ^ Elion, Gertrude (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. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  36. ^ US 4146715 
  37. ^ Vince, R. "A brief history of the development of Ziagen" Chemtracts 2008, 21, 127–134.
  38. ^ http://drugsynthesis.blogspot.co.uk/2011/11/laboratory-synthesis-of-acyclovir.html

Further reading

External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Aciclovir&oldid=617773583"