Aciclovir Explained

Aciclovir, also known as acyclovir,[1] is an antiviral medication.[2] It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles. Other uses include prevention of cytomegalovirus infections following transplant and severe complications of Epstein–Barr virus infection.[3] 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] [5] It appears to be safe during breastfeeding.[6] [7] Aciclovir is a nucleoside analogue that mimics guanosine.[4] It works by decreasing the production of the virus's DNA.[4]

Aciclovir was patented in 1974 by Burroughs Wellcome, and approved for medical use in 1981.[8] It is on the World Health Organization's List of Essential Medicines.[9] [10] It is available as a generic medication and is marketed under many brand names worldwide.[11] In 2021, it was the 169th most commonly prescribed medication in the United States, with more than 3million prescriptions.[12] [13]

Medical use

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

Its effectiveness in treating Epstein–Barr virus infections is less clear.[4] It has not been found to be useful for infectious mononucleosis due to Epstein-Barr virus.[17] Valaciclovir and 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 unpleasant side effects.[18]

Aciclovir taken by mouth does not appear to decrease the risk of pain after shingles.[19] In those with herpes of the eye, aciclovir may be more effective and safer than idoxuridine.[20] It is not clear if aciclovir eye drops are more effective than brivudine eye drops.

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 herpesviral encephalitis. It is also effective in systemic or traumatic herpes infections, eczema herpeticum and herpesviral 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.[21] 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.[22] 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.[23]

Pregnancy

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. Studies in rats in which they were given the equivalent to 63 times the standard steady-state humans concentrations of the drug[26] on day 10 of gestation showed head and tail anomalies.

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.[28] [29]

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, anaphylaxis, and Cotard's syndrome.

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.[30] [31] [32]

The aciclovir metabolite 9-Carboxymethoxymethylguanine (9-CMMG) has been shown to play a role in neurological adverse events, particularly in older people and those with reduced renal function.[33] [34] [35]

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. 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.

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.[36]

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.[28]

Interferon

Synergistic effects when administered with aciclovir and caution should be taken when administering aciclovir to patients receiving IV interferon.[37]

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.[38]

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.[39]

Mechanism of action

Aciclovir is converted by viral thymidine kinase to aciclovir monophosphate, which is then converted by host cell kinases to aciclovir triphosphate (ACV-TP, also known as aciclo-GTP). ACV-TP is a very potent inhibitor of viral DNA replication. ACV-TP competitively inhibits and inactivates the viral DNA polymerase.[40] Its monophosphate form also incorporates into the viral DNA, resulting in chain termination.[41] [42] [43]

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.[44] [45]

Microbiology

Aciclovir is active against most species in the herpesvirus family. In descending order of activity:[46] [47]

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. 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] 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.

Chemistry

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

In the first step shown, 2,6-dichloropurine was alkylated with 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 an amino group, which was then converted to an amide using nitrous 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

Aciclovir was seen as the start of a new era in antiviral therapy, as it is extremely selective and low in cytotoxicity.[2] 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.[53] [54] [55] 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.[50] Later, Schaeffer joined Burroughs Wellcome and continued the development of aciclovir with pharmacologist Gertrude B. Elion.[56] A U.S. patent on aciclovir listing Schaeffer as inventor was issued in 1979.[57] Vince later invented abacavir, an nRTI drug for HIV patients.[58] Elion was awarded the 1988 Nobel Prize in Medicine, partly for the development of aciclovir.[59]

A related prodrug form, valaciclovir came 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

Names

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.[11]

Further reading

Notes and References

  1. Web site: Kevin ES . The Aciclovir . Kevin . DE . 25 May 2017.
  2. News: de Clercq E, Field HJ . January 2006 . 5 October 2005 . Antiviral prodrugs – the development of successful prodrug strategies for antiviral chemotherapy. . Wiley-Blackwell. 147 . 1. 1–11. 16284630 . 1615839 . 10.1038/sj.bjp.0706446.
  3. Rafailidis PI, Mavros MN, Kapaskelis A, Falagas ME . Antiviral treatment for severe EBV infections in apparently immunocompetent patients . Journal of Clinical Virology . 49 . 3 . 151–157 . November 2010 . 20739216 . 10.1016/j.jcv.2010.07.008 .
  4. Web site: Acyclovir. The American Society of Health-System Pharmacists. Jan 1, 2015. live. https://web.archive.org/web/20150105113809/http://www.drugs.com/monograph/acyclovir.html. 2015-01-05.
  5. Web site: Prescribing medicines in pregnancy database. Australian Government. 22 April 2014. 3 March 2014. live. https://web.archive.org/web/20140408040902/http://www.tga.gov.au/hp/medicines-pregnancy.htm. 8 April 2014.
  6. Book: Hamilton R . Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. 2015. Jones & Bartlett Learning. 9781284057560. 59.
  7. Web site: Acyclovir use while Breastfeeding. 8 March 2016. Mar 10, 2015. 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. live. https://web.archive.org/web/20160305200238/http://www.drugs.com/breastfeeding/acyclovir.html. 5 March 2016.
  8. Book: Fischer J, Ganellin CR . Analogue-based Drug Discovery . 2006 . John Wiley & Sons . 9783527607495 . 504 .
  9. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 21st list 2019 . 2019 . 10665/325771 . World Health Organization . World Health Organization . Geneva . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO . free .
  10. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 22nd list (2021) . 2021 . 10665/345533 . World Health Organization . World Health Organization . Geneva . WHO/MHP/HPS/EML/2021.02 . free .
  11. Web site: Aciclovir. Drugs.com. 6 September 2015. live. https://web.archive.org/web/20150923225253/http://www.drugs.com/international/aciclovir.html. 23 September 2015.
  12. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
  13. Web site: Acyclovir - Drug Usage Statistics . ClinCalc . 14 January 2024.
  14. Book: Australian Medicines Handbook . 2013 . The Australian Medicines Handbook Unit Trust . 978-0-9805790-9-3 . 2013 . Adelaide . Rossi, S .
  15. Book: Joint Formulary Committee . British National Formulary (BNF) . 2013 . 978-0-85711-084-8 . 65 . London . Pharmaceutical Press . registration .
  16. Elad S, Zadik Y, Hewson I, Hovan A, Correa ME, Logan R, Elting LS, Spijkervet FK, Brennan MT . 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 . August 2010 . 20544224 . 10.1007/s00520-010-0900-3 . 2969472 .
  17. Gershburg E, Pagano JS . Epstein-Barr virus infections: prospects for treatment . The Journal of Antimicrobial Chemotherapy . 56 . 2 . 277–281 . August 2005 . 16006448 . 10.1093/jac/dki240 . 10.1.1.320.6721 .
  18. De Paor M, O'Brien K, Fahey T, Smith SM . Antiviral agents for infectious mononucleosis (glandular fever) . The Cochrane Database of Systematic Reviews . 2016 . 12 . CD011487 . December 2016 . 27933614 . 6463965 . 10.1002/14651858.CD011487.pub2 .
  19. Chen N, Li Q, Yang J, Zhou M, Zhou D, He L . Antiviral treatment for preventing postherpetic neuralgia . The Cochrane Database of Systematic Reviews . 2014 . 2 . CD006866 . February 2014 . 24500927 . 10.1002/14651858.CD006866.pub3 . 10583132 .
  20. Wilhelmus KR . Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis . The Cochrane Database of Systematic Reviews . 1 . CD002898 . January 2015 . 1 . 25879115 . 4443501 . 10.1002/14651858.CD002898.pub5 .
  21. Worrall G . Acyclovir in recurrent herpes labialis . BMJ . 312 . 7022 . 6 . January 1996 . 8555890 . 2349724 . 10.1136/bmj.312.7022.6 . live . https://web.archive.org/web/20070515183925/http://www.bmj.com/cgi/content/full/312/7022/6 . 2007-05-15 . – Editorial
  22. Spruance SL, Nett R, Marbury T, Wolff R, Johnson J, Spaulding T . 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 . July 2002 . 12069980 . 127288 . 10.1128/aac.46.7.2238-2243.2002 .
  23. Mascolinli M, Kort R . 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 . June 2010 . 20519025 . 2880255 . 10.1186/1758-2652-13-S1-S4 . free .
  24. Drugs for non-HIV viral infections . Treatment Guidelines from the Medical Letter . 3 . 32 . 23–32 . April 2005 . 15767977 .
  25. Kaplan JE, Benson C, Holmes KK, Brooks JT, Pau A, Masur H . 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 . April 2009 . 19357635 .
  26. Subject to the same conditions as before
  27. Book: Centers for Disease Control and Prevention. . Epidemiology and prevention of vaccine-preventable diseases. . 9th . Public Health Foundation . January 2006 . 171–192 .
  28. Web site: FDA . GSK . Acyclovir label . https://web.archive.org/web/20170908162359/https://www.accessdata.fda.gov/drugsatfda_docs/label/2001/18828s26s27lbl.pdf . 2017-09-08 . 2005 .
  29. Gartner LM, Morton J, Lawrence RA, Naylor AJ, O'Hare D, Schanler RJ, Eidelman AI . Breastfeeding and the use of human milk . Pediatrics . 115 . 2 . 496–506 . February 2005 . 15687461 . 10.1542/peds.2004-2491 . 5791615 . free .
  30. Razonable RR . Antiviral drugs for viruses other than human immunodeficiency virus . Mayo Clinic Proceedings . 86 . 10 . 1009–1026 . October 2011 . 21964179 . 3184032 . 10.4065/mcp.2011.0309 .
  31. Brigden D, Rosling AE, Woods NC . Renal function after acyclovir intravenous injection . The American Journal of Medicine . 73 . 1A . 182–185 . July 1982 . 6285711 . 10.1016/0002-9343(82)90087-0 .
  32. Sawyer MH, Webb DE, Balow JE, Straus SE . Acyclovir-induced renal failure. Clinical course and histology . The American Journal of Medicine . 84 . 6 . 1067–1071 . June 1988 . 3376977 . 10.1016/0002-9343(88)90313-0 .
  33. Helldén A, Odar-Cederlöf I, Diener P, Barkholt L, Medin C, Svensson JO, Säwe J, Ståhle L . 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 . June 2003 . 12748346 . 10.1093/ndt/gfg119 . free .
  34. Berry L, Venkatesan P . Aciclovir-induced neurotoxicity: Utility of CSF and serum CMMG levels in diagnosis . Journal of Clinical Virology . 61 . 4 . 608–610 . December 2014 . 25440915 . 10.1016/j.jcv.2014.09.001 .
  35. Chowdhury MA, Derar N, Hasan S, Hinch B, Ratnam S, Assaly R . Acyclovir-Induced Neurotoxicity: A Case Report and Review of Literature . American Journal of Therapeutics . 23 . 3 . e941–e943 . 2016 . 24942005 . 10.1097/MJT.0000000000000093 . 32983100 .
  36. Pottage JC, Kessler HA, Goodrich JM, Chase R, Benson CA, Kapell K, Levin S . In vitro activity of ketoconazole against herpes simplex virus . Antimicrobial Agents and Chemotherapy . 30 . 2 . 215–219 . August 1986 . 3021048 . 180521 . 10.1128/aac.30.2.215 .
  37. GlaxoSmithKline. Zovirax® (acyclovir sodium) for injection prescribing information. Research Triangle Park, NC; 2003 Nov
  38. Bach MC . Possible drug interaction during therapy with azidothymidine and acyclovir for AIDS . The New England Journal of Medicine . 316 . 9 . 547 . February 1987 . 3468354 . 10.1056/NEJM198702263160912 .
  39. Book: Baselt RC . Disposition of toxic drugs and chemicals in man. 2008. Biomedical Publications. Foster City, CA. 9780962652370. 29–31. 8th.
  40. Web site: VALTREX (valacyclovir hydrochloride) Caplets -GSKSource. gsksource.com. 2019-08-02.
  41. Web site: PRODUCT INFORMATION NAME OF THE DRUG OZVIR TABLETS. TGA eBusiness Services. Ranbaxy Australia Pty Ltd. 26 August 2011. 6 February 2014. PDF. live. https://web.archive.org/web/20160820205438/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-00595-3. 20 August 2016.
  42. Web site: Acyclovir (acyclovir) Capsule Acyclovir (acyclovir) Tablet [Genpharm Inc.]]. DailyMed. Genpharm Inc.. November 2006. 5 February 2014. live. https://web.archive.org/web/20140221224423/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=12ea5042-8ea6-4ee9-a734-684a73edb373. 21 February 2014.
  43. Web site: Aciclovir Tablets BP 400mg - Summary of Product Characteristics (SPC). electronic Medicines Compendium. Actavis UK Ltd. 20 August 2012. 5 February 2014. live. https://web.archive.org/web/20140222201708/http://www.medicines.org.uk/EMC/medicine/23721/SPC/Aciclovir+Tablets+BP+400mg. 22 February 2014.
  44. Book: Martindale: The Complete Drug Reference. Aciclovir. 7 August 2013. Pharmaceutical Press. Sweetman, S. 6 February 2014. http://www.medicinescomplete.com/mc/martindale/current/ms-1682-a.htm. London, UK.
  45. Piret J, Boivin G . Resistance of herpes simplex viruses to nucleoside analogues: mechanisms, prevalence, and management . Antimicrobial Agents and Chemotherapy . 55 . 2 . 459–472 . February 2011 . 21078929 . 3028810 . 10.1128/AAC.00615-10 .
  46. O'Brien JJ, Campoli-Richards DM . Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy . Drugs . 37 . 3 . 233–309 . March 1989 . 2653790 . 10.2165/00003495-198937030-00002 . 240858022 . free .
  47. Wagstaff AJ, Faulds D, Goa KL . Aciclovir. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic efficacy . Drugs . 47 . 1 . 153–205 . January 1994 . 7510619 . 10.2165/00003495-199447010-00009 . free .
  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 . 10.3329/dujps.v18i1.41421. free .
  49. Web site: Aciclovir Tablets BP 400mg - Summary of Product Characteristics (SmPC) - (emc). www.medicines.org.uk.
  50. Schaeffer HJ, Gurwara S, Vince R, Bittner S . Novel substrate of adenosine deaminase . Journal of Medicinal Chemistry . 14 . 4 . 367–369 . April 1971 . 5553754 . 10.1021/jm00286a024 .
  51. US . 4199574 . patent . 1980-04-22 . 1976-03-01 . 1974-09-02 . Schaeffer HJ . Methods and compositions for treating viral infections and guanine acyclic nucleosides . Burroughs Wellcome . . .
  52. Book: 10.1016/B978-0-12-411492-0.00034-1 . free . 34: Antiviral Drugs . Synthesis of Best-Seller Drugs . 2016 . Vardanyan R, Hruby V . 706–708 . Academic Press . 9780124114920 . 75449475 .
  53. Book: Garrison T . Oceanography: An Invitation to Marine Science, 3rd ed.. 1999. Wadsworth Publishing Company. Belmont, CA. 471.
  54. Sepčić K . 84041855 . Bioactive Alkylpyridinium Compounds from Marine Sponges . Toxin Reviews . 19 . 2 . 139–160 . 2000 . 10.1081/TXR-100100318 .
  55. Laport MS, Santos OC, Muricy G . Marine sponges: potential sources of new antimicrobial drugs . Current Pharmaceutical Biotechnology . 10 . 1 . 86–105 . January 2009 . 19149592 . 10.2174/138920109787048625 .
  56. Elion GB, Furman PA, Fyfe JA, de Miranda P, Beauchamp L, Schaeffer HJ . 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 . December 1977 . 202961 . 431864 . 10.1073/pnas.74.12.5716 . free . 1977PNAS...74.5716E .
  57. US. 4146715 . 2-Amido-9-(2-acyloxyethoxymethyl)hypoxanthines . Schaeffer HJ . Burrough Wellcome Co . 27 March 1979 . . .
  58. Vince R . 2008 . A brief history of the development of Ziagen . Chemtracts . 21 . 127–134 .
  59. Web site: The Nobel Prize - Gertrude B. Elion .
  60. Web site: Valacyclovir Hydrochloride Monograph for Professionals . Drugs.com . American Society of Health-System Pharmacists . 17 March 2019 .
  61. Web site: Drug Approval Package: Acyclovir and Hydrocortisone NDA #022436 . U.S. Food and Drug Administration (FDA) . 13 December 2019 . https://web.archive.org/web/20191213054239/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022436_acyclovir_hydrocortisone_toc.cfm . 13 December 2019 . live . 13 December 2019.
  62. Web site: Xerese- acyclovir and hydrocortisone cream . . 12 December 2019 . https://web.archive.org/web/20191213054630/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3b6ac164-0f1e-4f36-94a1-1fdb07d710f5 . 13 December 2019 . live . 12 December 2019.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Aciclovir".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.