Aciclovir

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Aciclovir
Systematic (IUPAC) name
2-Amino-1,9-dihydro-9-((2-hydroxyethoxy)methyl)-6H-purin-6-one
Clinical data
Trade namesZovirax
AHFS/Drugs.commonograph
MedlinePlusa681045
Licence dataUS FDA:link
Pregnancy cat.B3 (AU) B (US)
Legal statusPrescription Only (S4) (AU) POM (UK) -only (US)
RoutesIntravenous, oral, topical
Pharmacokinetic data
Bioavailability10–20% (oral)
Protein binding9–33%
MetabolismViral thymidine kinase
Half-life2.2–20 hours
ExcretionRenal
Identifiers
CAS number59277-89-3 YesY
ATC codeJ05AB01 D06BB03 S01AD03
PubChemCID 2022
DrugBankDB00787
ChemSpider1945 YesY
UNIIX4HES1O11F YesY
KEGGD00222 YesY
ChEBICHEBI:2453 YesY
ChEMBLCHEMBL184 YesY
Synonymsacycloguanosine
Chemical data
FormulaC8H11N5O3 
Mol. mass225.21 g/mol
Physical data
Melt. point256.5 °C (494 °F)
 YesY (what is this?)  (verify)
 
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Aciclovir
Systematic (IUPAC) name
2-Amino-1,9-dihydro-9-((2-hydroxyethoxy)methyl)-6H-purin-6-one
Clinical data
Trade namesZovirax
AHFS/Drugs.commonograph
MedlinePlusa681045
Licence dataUS FDA:link
Pregnancy cat.B3 (AU) B (US)
Legal statusPrescription Only (S4) (AU) POM (UK) -only (US)
RoutesIntravenous, oral, topical
Pharmacokinetic data
Bioavailability10–20% (oral)
Protein binding9–33%
MetabolismViral thymidine kinase
Half-life2.2–20 hours
ExcretionRenal
Identifiers
CAS number59277-89-3 YesY
ATC codeJ05AB01 D06BB03 S01AD03
PubChemCID 2022
DrugBankDB00787
ChemSpider1945 YesY
UNIIX4HES1O11F YesY
KEGGD00222 YesY
ChEBICHEBI:2453 YesY
ChEMBLCHEMBL184 YesY
Synonymsacycloguanosine
Chemical data
FormulaC8H11N5O3 
Mol. mass225.21 g/mol
Physical data
Melt. point256.5 °C (494 °F)
 YesY (what is this?)  (verify)
Structures of guanosine and aciclovir compared

Aciclovir (INN) (pron.: /ˈsklɵvɪər/) or acyclovir (USAN, former BAN), chemical name acycloguanosine, abbreviated as ACV,[1] is a guanosine analogue antiviral drug, marketed under trade names such as Cyclovir, Herpex, Acivir, Acivirax, Zovirax, Zoral, and Xovir. One of the most commonly used antiviral drugs, it 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).

Contents

History

Aciclovir was seen as the start of a new era in antiviral therapy,[1] 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.[2][3][4] 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.[5] Later, Schaffer joined Burroghs-Wellcome and continued the development of aciclovir with Pharmacologist Gertrude B. Elion.[6] Vince later went on to invent abacavir, the NNRTI drug for HIV patients.[7] Elion was awarded the 1988 Nobel Prize in Medicine, partly for the development of aciclovir. Dr. Richard Whitley, a University of Alabama at Birmingham researcher and pioneer in antiviral therapy, was the first to successfully use the drug in humans.

Pharmacology

Mechanism of action

Aciclovir differs from previous nucleoside analogues in containing only a partial nucleoside structure: the sugar ring is replaced with an open-chain structure. It is selectively converted into acyclo-guanosine monophosphate (acyclo-GMP) by viral thymidine kinase, which is far more effective (3000 times) in phosphorylation than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into the active triphosphate form, acyclo-guanosine triphosphate (acyclo-GTP), by cellular kinases. Acyclo-GTP has approximately 100 times greater affinity for viral than cellular polymerase. As a substrate, acyclo-GTP is incorporated into viral DNA, resulting in premature chain termination. Although aciclovir resembles a nucleotide, it has no 3' end. Therefore, after its incorporation into a growing DNA strand, no further nucleotides can be added to this strand. It has also been shown that viral enzymes cannot remove acyclo-GTP from the chain, which results in inhibition of further activity of DNA polymerase. Acyclo-GTP is fairly rapidly metabolised within the cell, possibly by cellular phosphatases.

In sum, aciclovir can be considered a prodrug: it is administered in an inactive (or less active) form and is metabolised into a more active species after administration.

Microbiology

Aciclovir is active against most species in the herpesvirus family. In descending order of activity:[8]

Activity is predominantly against HSV, and to a lesser extent VZV. It is only of limited efficacy against EBV and CMV. It is inactive against latent viruses in nerve ganglia.

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 and/or DNA polymerase, altering substrate sensitivity.[9] Aciclovir has also shown cross-resistance with valaciclovir and famciclovir.

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%.[10] The elimination half-life of aciclovir is approximately 3 hours. It is renally excreted, partly by glomerular filtration and partly by tubular secretion.

The poor oral bioavailability may also be improved by administering valaciclovir, which has an oral bioavailability of about 55%. Valaciclovir is then converted to aciclovir by esterases via hepatic first-pass metabolism.

Clinical use

400 mg pills of aciclovir
Photo of pure Aciclovir

Indications

Aciclovir is indicated for the treatment of HSV and VZV infections, including:[11]

HIV-1 progression can be delayed by using aciclovir, according to study led by Dr Jairam Lingappa. Effective in 16% of cases, it can delay the HAART treatment by 1–2 years. University of Washington, Seattle. During a 2 year trial, 284 people progressed with the HIV-1, versus 324 who had not been treated with aciclovir.[13] It has been claimed that the evidence for the effectiveness of topically applied cream for recurrent labial outbreaks is weak.[14] 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.[15] However, oral therapy for episodes was found to be inappropriate for most nonimmunocompromised patients based on costs and benefits, presumably in countries where aciclovir is only available on prescription. There is evidence for an oral prophylactic role in preventing recurrences.

Dosage forms

Aciclovir is commonly marketed as tablets (200 mg, 400 mg, 800 mg and 1 gram), topical cream (5%), intravenous injection (25 mg/mL) and ophthalmic ointment (3%). Cream preparations are used primarily for labial herpes simplex. The intravenous injection is used when high concentrations of aciclovir are required. The ophthalmic ointment preparation is only used for herpes simplex keratitis.

Adverse effects

Systemic therapy

Common adverse drug reactions (≥1% of patients) associated with systemic aciclovir therapy (oral or IV) include: nausea, vomiting, diarrhea and/or 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/or weakness. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenia, leukopenia, crystalluria, anorexia, fatigue, hepatitis, Stevens–Johnson syndrome, toxic epidermal necrolysis and/or anaphylaxis.[11]

Additional common adverse effects, when aciclovir is administered IV, include encephalopathy (1% of patients) and injection site reactions. The injection formulation is alkaline (pH 11), and extravasation may cause local tissue pain and irritation.[11] Renal impairment has been reported when aciclovir is given in large, fast doses intravenously, due to the crystallisation of aciclovir in the kidneys.[16][17]

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.[11] 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.[11]

Toxicity

Since cellular DNA can incorporate aciclovir into itself, the drug acts as a chromosome mutagen; therefore it "...should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus..."[18] However, it has not been shown to have any teratogenic or carcinogenic effects and is frequently prescribed for pregnant women, to prevent transmission of HSV to the neonate.[citation needed] The acute toxicity (LD50) of aciclovir when given orally is greater than 1 g/kg, due to its low oral bioavailability.[citation needed] Patients with renal impairment often exhibit elimination half-lives for the drug that are five to six times longer than in those with normal renal function, leading to accumulation of aciclovir in the plasma and the likelihood of development of toxic reactions, such as lethargy, confusion and myoclonus.[19]

Cotard delusion has also been the result of adverse drug reactions to aciclovir. The symptoms were associated with high serum concentrations of 9-carboxymethoxymethylguanine (CMMG), the principal metabolite of aciclovir.

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.[19]

See also

References

  1. ^ 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 (Wiley-Blackwell) 147 (1): pp. 1–11. January 2006. doi:10.1038/sj.bjp.0706446. PMC 1615839. PMID 16284630
  2. ^ Garrison, Tom (1999). Oceanography: An Invitation to Marine Science, 3rd ed.. Belmont, CA: Wadsworth Publishing Company. pp. 471.
  3. ^ Sepčić, K. (2000). "Bioactive Alkylpyridinium Compounds from Marine Sponges". Toxin Reviews 19 (2): 139–160. doi:10.1081/TXR-100100318. edit
  4. ^ 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
  5. ^ 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.
  6. ^ 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC431864/.
  7. ^ Vince, R. "A brief history of the development of Ziagen" Chemtracts 2008, 21, 127–134.
  8. ^ O'Brien JJ, Campoli-Richards DM. (1989). "Aciclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy". Drugs 37 (3): 233–309. PMID 2653790.
  9. ^ Sweetman S, editor. Martindale: The complete drug reference. 34th ed. London: Pharmaceutical Press; 2004. ISBN 0-85369-550-4
  10. ^ Aciclovir Tablets BP 400mg - Summary of Product Characteristics (SPC) - (eMC)
  11. ^ a b c d e Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  12. ^ 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.
  13. ^ "HIV illness 'delayed by' herpes drug aciclovir". BBC News Onine. 15 February 2010. http://news.bbc.co.uk/2/hi/health/8512412.stm. Retrieved 20. May 2010.
  14. ^ Graham Worrall (July 1996). "Evidence for efficacy of topical acyclovir in recurrent herpes labialis is weak". BMJ 313 (7048): 46. doi:10.1136/bmj.313.7048.46a. PMC 2351426. PMID 8664786. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2351426/. – Letter
  15. ^ 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. http://www.bmj.com/cgi/content/full/312/7022/6. – Editorial
  16. ^ 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.
  17. ^ 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.
  18. ^ GLOBAL ACYCLOVIR, Medsafe Website
  19. ^ a b R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 29–31.

Further reading

External links