Jump to content

Aciclovir

From Wikipedia, the free encyclopedia

Aciclovir
Clinical data
Pronunciation/eɪˈsaɪkloʊvɪər/
Trade namesZovirax, others[1]
Other namesAcycloguanosine, acyclovir (BANUK), acyclovir (USANUS)
AHFS/Drugs
MedlinePlusa681045
License data
Pregnancy
category
  • AU:B3
Routes of
administration		Intravenous,by mouth,topical,eye ointment
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability15–20% (by mouth)[3]
Protein binding9–33%[3]
MetabolismLiver
Eliminationhalf-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
PubChemCID
PubChemSID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard(EPA)
ECHA InfoCard100.056.059Edit this at Wikidata
Chemical and physical data
FormulaC8H11N5O3
Molar mass225.208g·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-NcheckY
(verify)

Aciclovir,also known asacyclovir,[4]is anantiviral medication.[5]It is primarily used for the treatment ofherpes simplex virusinfections,chickenpox,andshingles.[6]Other uses include prevention ofcyt Omega lovirusinfections following transplant and severe complications ofEpstein–Barr virusinfection.[6][7]It can be taken by mouth, applied as a cream, orinjected.[6]

Common side effects include nausea and diarrhea.[6]Potentially serious side effects include kidney problems andlow platelets.[6]Greater care is recommended in those with poor liver or kidney function.[6]It is generally considered safe for use inpregnancywith no harm having been observed.[6][8]It appears to be safe duringbreastfeeding.[9][10]Aciclovir is anucleoside analoguethat mimicsguanosine.[6]It works by decreasing the production of the virus'sDNA.[6]

Aciclovir was patented in 1974 byBurroughs Wellcome,and approved for medical use in 1981.[11]It is on theWorld Health Organization's List of Essential Medicines.[12]It is available as ageneric medicationand is marketed under many brand names worldwide.[1]In 2022, it was the 134th most commonly prescribed medication in the United States, with more than 4million prescriptions.[13][14]

Medical use

[edit]
400 mg pills of aciclovir

Aciclovir is used for the treatment ofherpes simplex virus(HSV) andvaricella zoster virusinfections, including:[3][15][16]

Its effectiveness in treatingEpstein–Barr virusinfections is less clear.[6]It has not been found to be useful forinfectious mononucleosisdue to Epstein-Barr virus.[18]Valaciclovirand 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 unpleasantside effects.[19]

Aciclovir taken by mouth does not appear to decrease the risk of pain after shingles.[20]In those with herpes of the eye, aciclovir may be more effective and safer thanidoxuridine.[21]It is not clear if aciclovir eye drops are more effective thanbrivudineeye drops.[21]

Intravenousaciclovir 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,chickenpoxandherpesviral encephalitis.It is also effective in systemic or traumatic herpes infections, eczema herpeticum andherpesviral 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.[22]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.[23]Aciclovir trials show that this agent has no role in preventingHIVtransmission, but it can help slow HIV disease progression in people not takinganti-retroviral therapy (ART).This finding emphasizes the importance of testing simple, inexpensive non-ART strategies, such as aciclovir andcotrimoxazole,in people with HIV.[24]

Pregnancy

[edit]

The CDC and others have declared that during severe recurrent or first episodes of genital herpes, aciclovir may be used.[25]For severe HSV infections (especially disseminated HSV), IV aciclovir may also be used.[26]

Studies in mice, rabbits and rats (with doses more than 10 times the equivalent of that used in humans) given duringorganogenesishave failed to demonstrate birth defects.[27]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.[27]

Aciclovir is recommended by the CDC for treatment ofvaricelladuring pregnancy, especially during the second and third trimesters.[28]

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.[29][30]

Adverse effects

[edit]

Systemic therapy

[edit]

Commonadverse 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,hallucinationshave 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,anaphylaxis,[15]andCotard's syndrome.

Intravenous aciclovir may cause reversiblenephrotoxicityin 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.[31][32][33]

The aciclovir metabolite9-Carboxymethoxymethylguanine(9-CMMG) has been shown to play a role in neurological adverse events, particularly in older people and those with reduced renal function.[34][35][36]

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 includeerythemaor itch.[15]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 superficialpunctate keratitisor allergic reactions.[15]

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 has not been clinically established and more studies need to be done to evaluate the true potential of this synergy.[37]

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.[29]

Interferon:Synergistic effects when administered with aciclovir and caution should be taken when administering aciclovir to patients receiving IV interferon.[38]

Zidovudine:Although administered often with aciclovir in HIV patients,neurotoxicityhas 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.[39]

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.[40]

Mechanism of action

[edit]
Structures ofguanosineand aciclovir compared
Mechanisms (HSV DNA polymerase inhibition and HSV DNA incorporation) of acyclovir action

Aciclovir is converted by viralthymidine kinaseto aciclovir monophosphate, which is then converted by host cellkinasesto aciclovir triphosphate (ACV-TP, also known as aciclo-GTP).[27]ACV-TP is a very potent inhibitor ofviralDNA replication.ACV-TP competitively inhibits and inactivates the viralDNA polymerase.[41]Its monophosphate form also incorporates into the viral DNA, resulting inchain termination.[27][42][43]

Resistance

[edit]

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 withacquired immunodeficiency syndromedue 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.[44][45]

Microbiology

[edit]
Varicella zoster virus-produced plaques in monolayers ofMRC-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 theherpesvirusfamily. In descending order of activity:[46][47]

Pharmacokinetics

[edit]

Aciclovir is poorly water-soluble and has poor oralbioavailability(15–30%), henceintravenousadministration 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.[48]Aciclovir has a high distribution rate; protein binding is reported to range from 9 to 33%.[49]Theelimination half-life(t1/2) of aciclovir depends according to age group; neonates have a t1/2of 4 hours, children 1–12 years have a t1/2of 2–3 hours whereas adults have a t1/2of 3 hours.[3]

Chemistry

[edit]

Details of the synthesis of aciclovir were first published by scientists from theUniversity at Buffalo.[50]

In the first step shown, 2,6-dichloropurinewasalkylatedwith 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 anamino group,which was then converted to an amide usingnitrous acid.Finally, the remaining chlorine was replaced by the amino group of aciclovir using ammonia in methanol.[51]This synthesis and other methods for preparing the compound have been reviewed.[52]

History

[edit]

Aciclovir was seen as the start of a new era in antiviral therapy, as it is extremely selective and low incytotoxicity.[5]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.Nucleosidesisolated from a Caribbeansponge,Cryptotethya crypta,were the basis for the synthesis of aciclovir.[53][54][55]It was codiscovered by Howard Schaeffer following his work withRobert Vince,S. Bittner and S. Gurwara on the adenosine analog acycloadenosine which showed promising antiviral activity.[50]Later, Schaeffer joinedBurroughs Wellcomeand continued the development of aciclovir withpharmacologistGertrude B. Elion.[56]A U.S. patent on aciclovir listing Schaeffer as inventor was issued in 1979.[57]Vince later inventedabacavir,annRTIdrug for HIV patients.[58]Elion was awarded the 1988Nobel Prize in Medicine,partly for the development of aciclovir.[59]

A relatedprodrugform,valaciclovircame into medical use in 1995. It is converted to aciclovir in the body after absorption.[60]

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).[61][62]

Society and culture

[edit]

Names

[edit]

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]

Notes

[edit]
  1. ^Subject to the same conditions as before

References

[edit]
  1. ^abc"Aciclovir".Drugs.Archivedfrom the original on 23 September 2015.Retrieved6 September2015.
  2. ^"Skin health".Health Canada.9 May 2018.Retrieved13 April2024.
  3. ^abcd"Zovirax (acyclovir) dosing, indications, interactions, adverse effects, and more".Medscape Reference.WebMD.Archivedfrom the original on 19 February 2014.Retrieved5 February2014.
  4. ^Kevin ES."The Aciclovir"(in German). Kevin.Retrieved25 May2017.
  5. ^abde Clercq E, Field HJ (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.PMC1615839.PMID16284630.
  6. ^abcdefghij"Acyclovir".The American Society of Health-System Pharmacists.Archivedfrom the original on 2015-01-05.RetrievedJan 1,2015.
  7. ^Rafailidis PI, Mavros MN, Kapaskelis A, Falagas ME (November 2010). "Antiviral treatment for severe EBV infections in apparently immunocompetent patients".Journal of Clinical Virology.49(3): 151–157.doi:10.1016/j.jcv.2010.07.008.PMID20739216.
  8. ^"Prescribing medicines in pregnancy database".Australian Government.3 March 2014.Archivedfrom the original on 8 April 2014.Retrieved22 April2014.
  9. ^Hamilton R (2015).Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition.Jones & Bartlett Learning. p. 59.ISBN9781284057560.
  10. ^"Acyclovir use while Breastfeeding".Mar 10, 2015.Archivedfrom the original on 5 March 2016.Retrieved8 March2016.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
  11. ^Fischer J, Ganellin CR (2006).Analogue-based Drug Discovery.John Wiley & Sons. p. 504.ISBN9783527607495.
  12. ^World Health Organization(2023).The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023).Geneva: World Health Organization.hdl:10665/371090.WHO/MHP/HPS/EML/2023.02.
  13. ^"The Top 300 of 2022".ClinCalc.Archivedfrom the original on 30 August 2024.Retrieved30 August2024.
  14. ^"Acyclovir Drug Usage Statistics, United States, 2013 - 2022".ClinCalc.Retrieved30 August2024.
  15. ^abcdRossi, S, ed. (2013).Australian Medicines Handbook(2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust.ISBN978-0-9805790-9-3.
  16. ^Joint Formulary Committee (2013).British National Formulary (BNF)(65 ed.). London: Pharmaceutical Press.ISBN978-0-85711-084-8.
  17. ^Elad S, Zadik Y, Hewson I, Hovan A, Correa ME, Logan R, et al. (August 2010). "A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea".Supportive Care in Cancer.18(8): 993–1006.doi:10.1007/s00520-010-0900-3.PMID20544224.S2CID2969472.
  18. ^Gershburg E, Pagano JS (August 2005). "Epstein-Barr virus infections: prospects for treatment".The Journal of Antimicrobial Chemotherapy.56(2): 277–281.CiteSeerX10.1.1.320.6721.doi:10.1093/jac/dki240.PMID16006448.
  19. ^De Paor M, O'Brien K, Fahey T, Smith SM (December 2016)."Antiviral agents for infectious mononucleosis (glandular fever)".The Cochrane Database of Systematic Reviews.2016(12): CD011487.doi:10.1002/14651858.CD011487.pub2.PMC6463965.PMID27933614.
  20. ^Chen N, Li Q, Yang J, Zhou M, Zhou D, He L (February 2014)."Antiviral treatment for preventing postherpetic neuralgia".The Cochrane Database of Systematic Reviews.2014(2): CD006866.doi:10.1002/14651858.CD006866.pub3.PMC10583132.PMID24500927.
  21. ^abWilhelmus KR (January 2015)."Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis".The Cochrane Database of Systematic Reviews.1(1): CD002898.doi:10.1002/14651858.CD002898.pub5.PMC4443501.PMID25879115.
  22. ^Worrall G (January 1996)."Acyclovir in recurrent herpes labialis".BMJ.312(7022): 6.doi:10.1136/bmj.312.7022.6.PMC2349724.PMID8555890.Archivedfrom the original on 2007-05-15.– Editorial
  23. ^Spruance SL, Nett R, Marbury T, Wolff R, Johnson J, Spaulding T (July 2002)."Acyclovir cream for treatment of herpes simplex labialis: results of two randomized, double-blind, vehicle-controlled, multicenter clinical trials".Antimicrobial Agents and Chemotherapy.46(7): 2238–2243.doi:10.1128/aac.46.7.2238-2243.2002.PMC127288.PMID12069980.
  24. ^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".Journal of the International AIDS Society.13(Suppl 1): S4.doi:10.1186/1758-2652-13-S1-S4.PMC2880255.PMID20519025.
  25. ^"Drugs for non-HIV viral infections".Treatment Guidelines from the Medical Letter.3(32): 23–32. April 2005.PMID15767977.
  26. ^Kaplan JE, Benson C, Holmes KK, Brooks JT, Pau A, Masur H (April 2009)."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".MMWR. Recommendations and Reports.58(RR-4): 1–207, quiz CE1–4.PMID19357635.
  27. ^abcd"PRODUCT INFORMATION NAME OF THE DRUG OZVIR TABLETS"(PDF).TGA eBusiness Services.Ranbaxy Australia Pty Ltd. 26 August 2011.Archivedfrom the original on 20 August 2016.Retrieved6 February2014.
  28. ^Centers for Disease Control and Prevention. (January 2006).Epidemiology and prevention of vaccine-preventable diseases(9th ed.). Public Health Foundation. pp. 171–192.
  29. ^ab"Acyclovir label"(PDF).GSK.FDA. 2005. Archived fromthe original(PDF)on 2017-09-08.
  30. ^Gartner LM, Morton J, Lawrence RA, Naylor AJ, O'Hare D, Schanler RJ, et al. (February 2005)."Breastfeeding and the use of human milk".Pediatrics.115(2): 496–506.doi:10.1542/peds.2004-2491.PMID15687461.S2CID5791615.
  31. ^Razonable RR (October 2011)."Antiviral drugs for viruses other than human immunodeficiency virus".Mayo Clinic Proceedings.86(10): 1009–1026.doi:10.4065/mcp.2011.0309.PMC3184032.PMID21964179.
  32. ^Brigden D, Rosling AE, Woods NC (July 1982). "Renal function after acyclovir intravenous injection".The American Journal of Medicine.73(1A): 182–185.doi:10.1016/0002-9343(82)90087-0.PMID6285711.
  33. ^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): 1067–1071.doi:10.1016/0002-9343(88)90313-0.PMID3376977.
  34. ^Helldén A, Odar-Cederlöf I, Diener P, Barkholt L, Medin C, Svensson JO, et al. (June 2003)."High serum concentrations of the acyclovir main metabolite 9-carboxymethoxymethylguanine in renal failure patients with acyclovir-related neuropsychiatric side effects: an observational study".Nephrology, Dialysis, Transplantation.18(6): 1135–1141.doi:10.1093/ndt/gfg119.PMID12748346.
  35. ^Berry L, Venkatesan P (December 2014). "Aciclovir-induced neurotoxicity: Utility of CSF and serum CMMG levels in diagnosis".Journal of Clinical Virology.61(4): 608–610.doi:10.1016/j.jcv.2014.09.001.PMID25440915.
  36. ^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–e943.doi:10.1097/MJT.0000000000000093.PMID24942005.S2CID32983100.
  37. ^Pottage JC, Kessler HA, Goodrich JM, Chase R, Benson CA, Kapell K, et al. (August 1986)."In vitro activity of ketoconazole against herpes simplex virus".Antimicrobial Agents and Chemotherapy.30(2): 215–219.doi:10.1128/aac.30.2.215.PMC180521.PMID3021048.
  38. ^GlaxoSmithKline. Zovirax® (acyclovir sodium) for injection prescribing information. Research Triangle Park, NC; 2003 Nov
  39. ^Bach MC (February 1987). "Possible drug interaction during therapy with azidothymidine and acyclovir for AIDS".The New England Journal of Medicine.316(9): 547.doi:10.1056/NEJM198702263160912.PMID3468354.
  40. ^Baselt RC (2008).Disposition of toxic drugs and chemicals in man(8th ed.). Foster City, CA: Biomedical Publications. pp. 29–31.ISBN9780962652370.
  41. ^"VALTREX (valacyclovir hydrochloride) Caplets -GSKSource".gsksource.Retrieved2019-08-02.
  42. ^"Acyclovir (acyclovir) Capsule Acyclovir (acyclovir) Tablet [Genpharm Inc.]".DailyMed.Genpharm Inc. November 2006.Archivedfrom the original on 21 February 2014.Retrieved5 February2014.
  43. ^"Aciclovir Tablets BP 400mg - Summary of Product Characteristics (SPC)".electronic Medicines Compendium.Actavis UK Ltd. 20 August 2012.Archivedfrom the original on 22 February 2014.Retrieved5 February2014.
  44. ^Sweetman, S, ed. (7 August 2013)."Aciclovir".Martindale: The Complete Drug Reference.London, UK: Pharmaceutical Press.Retrieved6 February2014.
  45. ^Piret J, Boivin G (February 2011)."Resistance of herpes simplex viruses to nucleoside analogues: mechanisms, prevalence, and management".Antimicrobial Agents and Chemotherapy.55(2): 459–472.doi:10.1128/AAC.00615-10.PMC3028810.PMID21078929.
  46. ^O'Brien JJ, Campoli-Richards DM (March 1989)."Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy".Drugs.37(3): 233–309.doi:10.2165/00003495-198937030-00002.PMID2653790.S2CID240858022.
  47. ^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.PMID7510619.
  48. ^Karmoker JR, Hasan I, Ahmed N, Saifuddin M, Reza MS (2019)."Development and Optimization of Acyclovir Loaded Mucoadhesive Microspheres by Box -Behnken Design".Dhaka University Journal of Pharmaceutical Sciences.18(1): 1–12.doi:10.3329/dujps.v18i1.41421.
  49. ^"Aciclovir Tablets BP 400mg - Summary of Product Characteristics (SmPC) - (emc)".medicines.org.uk.
  50. ^abSchaeffer HJ, Gurwara S, Vince R, Bittner S (April 1971). "Novel substrate of adenosine deaminase".Journal of Medicinal Chemistry.14(4): 367–369.doi:10.1021/jm00286a024.PMID5553754.
  51. ^US patent 4199574,Schaeffer HJ, "Methods and compositions for treating viral infections and guanine acyclic nucleosides", published 1980-04-22, assigned to Burroughs Wellcome.
  52. ^Vardanyan R, Hruby V (2016). "34: Antiviral Drugs".Synthesis of Best-Seller Drugs.Academic Press. pp. 706–708.doi:10.1016/B978-0-12-411492-0.00034-1.ISBN9780124114920.S2CID75449475.
  53. ^Garrison T (1999).Oceanography: An Invitation to Marine Science, 3rd ed.Belmont, CA: Wadsworth Publishing Company. p. 471.
  54. ^Sepčić K (2000). "Bioactive Alkylpyridinium Compounds from Marine Sponges".Toxin Reviews.19(2): 139–160.doi:10.1081/TXR-100100318.S2CID84041855.
  55. ^Laport MS, Santos OC, Muricy G (January 2009). "Marine sponges: potential sources of new antimicrobial drugs".Current Pharmaceutical Biotechnology.10(1): 86–105.doi:10.2174/138920109787048625.PMID19149592.
  56. ^Elion GB, Furman PA, Fyfe JA, de Miranda P, Beauchamp L, Schaeffer HJ (December 1977)."Selectivity of action of an antiherpetic agent, 9-(2-hydroxyethoxymethyl) guanine".Proceedings of the National Academy of Sciences of the United States of America.74(12): 5716–5720.Bibcode:1977PNAS...74.5716E.doi:10.1073/pnas.74.12.5716.PMC431864.PMID202961.
  57. ^US 4146715,Schaeffer HJ, "2-Amido-9-(2-acyloxyethoxymethyl)hypoxanthines", issued 27 March 1979, assigned to Burrough Wellcome Co.
  58. ^Vince R (2008). "A brief history of the development of Ziagen".Chemtracts.21:127–134.
  59. ^"The Nobel Prize - Gertrude B. Elion".
  60. ^"Valacyclovir Hydrochloride Monograph for Professionals".Drugs.American Society of Health-System Pharmacists.Retrieved17 March2019.
  61. ^"Drug Approval Package: Acyclovir and Hydrocortisone NDA #022436".U.S.Food and Drug Administration(FDA).13 December 2019.Archivedfrom the original on 13 December 2019.Retrieved13 December2019.Public DomainThis article incorporates text from this source, which is in thepublic domain.
  62. ^"Xerese- acyclovir and hydrocortisone cream".DailyMed.12 December 2019.Archivedfrom the original on 13 December 2019.Retrieved12 December2019.

Further reading

[edit]
Retrieved from "https://en.wikipedia.org/w/index.php?title=Aciclovir&oldid=1248570312"