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Valaciclovir (INN) or valacyclovir (USAN) is an antiviral drug used in the management of herpes simplex, herpes zoster (shingles), and herpes B. It is a prodrug, being converted in vivo to aciclovir. It is marketed by GlaxoSmithKline under the trade names Valtrex and Zelitrex. Valaciclovir has been available as a generic drug in the U.S. since November 25, 2009.^[1]

Pharmacology

Mechanism of action

Valaciclovir belongs from a family of molecules first described and patented by P.Cornaglia Ferraris in 1982 (patents EP0077460 A2, CA1258149A1, DE3273785D1, EP0077460A3, EP0077460B1, US4567182). Valaciclovir is a prodrug, an esterified version of aciclovir that has greater oral bioavailability (about 55%) than aciclovir (10–20%). It is converted by esterases to the active drug aciclovir, as well as the amino acid valine, via hepatic first-pass metabolism. Aciclovir is selectively converted into a monophosphate form by viral thymidine kinase, which is far more effective (3000 times) in phosphorylation of aciclovir than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into the active triphosphate form, aciclo-GTP, by cellular kinases. Aciclo-GTP is a very potent inhibitor of viral DNA polymerase; it has approximately 100 times higher affinity to viral than cellular polymerase. Its monophosphate form also incorporates into the viral DNA, resulting in chain termination. It has also been shown that the viral enzymes cannot remove aciclo-GMP from the chain, which results in inhibition of further activity of DNA polymerase. Aciclo-GTP is fairly rapidly metabolised within the cell, possibly by cellular phosphatases.^[2]

Microbiology

Aciclovir, the active metabolite of valaciclovir, is active against most species in the herpesvirus family. In descending order of activity:^[3]

Herpes simplex virus type I (HSV-1)
Herpes simplex virus type II (HSV-2)
Varicella zoster virus (VZV)
Epstein–Barr virus (EBV)
Cytomegalovirus (CMV)

The drug is predominantly active against HSV, and to a lesser extent VZV. It is only of limited efficacy against EBV and CMV; however, valacyclovir has recently been shown to lower or eliminate the presence of the Epstein–Barr virus in subjects afflicted with acute mononucleosis, leading to a significant decrease in the severity of symptoms.^[4]^[5]^[6] It is inactive against latent viruses in nerve ganglia^{[citation needed]}.

To date,^[when?] resistance to valaciclovir has not been clinically significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase, and mutations to viral thymidine kinase and/or DNA polymerase, altering substrate sensitivity.^[7]

It also is used for herpes B virus postexposure prophylaxis.^[8]

Ingredients and dosage

Valtrex is offered in 250 mg, 500 mg, and 1 gram tablets, the active ingredient being valacyclovir hydrochloride, with the inactive ingredients carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide.^[9]

Clinical use

Indications

Valtrex brand valaciclovir 500mg tablets

Valaciclovir is indicated for the treatment of HSV and VZV infections, including:^[10]

Oral and genital herpes simplex (treatment and prophylaxis)
Reduction of HSV transmission from people with recurrent infection to uninfected individuals
Herpes zoster (shingles): the typical dosage for treatment of herpes is 1,000 mg orally three times a day for seven consecutive days. ^[11]

Prevention of cytomegalovirus following organ transplantation
Prophylaxis against herpesviruses in immunocompromised patients (such as patients undergoing cancer chemotherapy)^[12]

It has shown promise as a treatment for infectious mononucleosis,^[4]^[5]^[6] and is preventively administered in suspected cases of herpes B virus exposure.^{[citation needed]}

Adverse effects

Common adverse drug reactions (≥1% of patients) associated with valaciclovir therapy are the same as for aciclovir, its active metabolite, and include: nausea, vomiting, diarrhea and headache. Infrequent adverse effects (0.1–1% of patients) include: agitation, vertigo, confusion, dizziness, edema, arthralgia, sore throat, constipation, abdominal pain, rash, weakness and/or renal impairment. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenia, leukopenia, tremor, ataxia, encephalopathy, psychotic symptoms, crystalluria, anorexia, fatigue, hepatitis, Stevens–Johnson syndrome, toxic epidermal necrolysis and/or anaphylaxis.^[10]

References

^ Ahmed, Rumman (November 27, 2009). "Ranbaxy Launches Generic Valtrex in U.S.". The Wall Street Journal. Retrieved January 16, 2010.
^ http://www.uscnk.us/protein-antibody-elisa/Valaciclovir-%28VCV%29-V511.htm
^ 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. PMID 2653790.
^ ^a ^b Balfour et al. (December 2005) A controlled trial of valacyclovir in infectious mononucleosis. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC., December 18, 2005. Abstract V1392
^ ^a ^b Simon, Michael W.; Robert G. Deeter; Britt Shahan (March 2003). "The Effect of Valacyclovir and Prednisolone in Reducing Symptoms of EBV Illness In Children: A Double-Blind, Placebo-Controlled Study" (PDF). International Pediatrics 18 (3): 164–169. ^{[dead link]}
^ ^a ^b Balfour HH, Hokanson KM, Schacherer RM, et al. (May 2007). "A virologic pilot study of valacyclovir in infectious mononucleosis". Journal of Clinical Virology 39 (1): 16–21. doi:10.1016/j.jcv.2007.02.002. PMID 17369082.
^ Sweetman, Sean C., ed. (2005). Martindale: the complete drug reference (34th ed.). London: Pharmaceutical Press. ISBN 0-85369-550-4. OCLC 56903116. ^{[page needed]}
^ "B Virus—First Aid and Treatment—Herpes B—CDC". Retrieved June 6, 2015.
^ "Valtrex Prescribing Information" (PDF). GlaxoSmithKline. September 2008. Retrieved May 7, 2009.
^ ^a ^b Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3^{[page needed]}
^ Lille, H. Martina; Wassilew, Sawko W. (2006). "Antiviral therapies of shingles in dermatology". In Gross, Gerd; Doerr, H.W. Herpes zoroster: recent aspects of diagnosis and control. Monographs in virology 26. Basel (Switzerland): Karger Publishers. p. 124. ISBN 978-3-8055-7982-7. Retrieved January 1, 2012.
^ 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.

UpToDate Contents

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1. バラシクロビル：概要 valacyclovir an overview
2. 性器単純ヘルペスウイルス感染の治療 treatment of genital herpes simplex virus infection
3. 免疫正常患者における帯状疱疹の治療 treatment of herpes zoster in the immunocompetent host
4. 免疫正常患者における単純ヘルペスウイルス1型感染の治療 treatment of herpes simplex virus type 1 infection in immunocompetent patients
5. 腎移植レシピエントにおけるサイトメガロウイルス感染 cytomegalovirus infection in renal transplant recipients

English Journal

Impact of the duration of antiviral prophylaxis on rates of varicella-zoster virus reactivation disease in autologous hematopoietic cell transplantation recipients.

Truong Q1, Veltri L, Kanate AS, Hu Y, Craig M, Hamadani M, Cumpston A.Author information 1Section of Hematology/Oncology, MBRCC, West Virginia University, Morgantown, WV, USA.AbstractVaricella-zoster virus (VZV) reactivation is a relatively common cause of morbidity following autologous hematopoietic cell transplant (auto-HCT). The Centers for Disease Control in 2009 recommended extending VZV prophylaxis for 1 year post-transplantation. We retrospectively analyzed rates of VZV reactivation following auto-HCT at our transplant center prior to and after the implementation of extended antiviral prophylaxis in June 2008. The study population was divided into three different cohorts according to the length of VZV prophylaxis as following: (1) prophylaxis until neutrophil recovery to ≥500/μL (n = 77), (2) prophylaxis for 6 months (n = 12), or (3) 12 months (n = 40) post-auto-HCT. All patients received acyclovir 400 mg oral or intravenously twice daily or valacyclovir 500 mg oral daily. For patients in whom VZV reactivation occurred, data was collected on severity of infection, time of onset, treatment, and any associated complications. One hundred twenty-nine patients undergoing auto-HCT between January 1, 2004 and January 31, 2010 were included in the study. There was a significant difference in the rates of VZV reactivation between the neutrophil recovery and 12 months prophylaxis cohorts at 14 % (n = 11) and 2 % (n = 1) (P = 0.04), respectively. VZV reactivation rate in the 6-month prophylaxis group was 17 % (n = 2), but did not reach statistical significance due to small numbers. In the subset of auto-HCT patients treated with bortezomib, 13 % (n = 2) developed VZV reactivation in the neutrophil recovery group, while no events occurred in the other two cohorts. Complications of VZV reactivation include post-herpetic neuralgia (n = 5), severe pain (n = 3), scarring (n = 1), and motor weakness (n = 1); two patients required hospitalization and three patients developed disseminated zoster. Our limited retrospective analysis suggests a significant reduction in rates of post-auto-HCT rates of VZV reactivation with extended 12 months antiviral prophylaxis. VZV reactivation is a significant complication post-auto-HCT, and extended prophylaxis appears to be safe and effective in this setting.
Annals of hematology.Ann Hematol.2014 Apr;93(4):677-82. doi: 10.1007/s00277-013-1913-z. Epub 2013 Oct 6.
Varicella-zoster virus (VZV) reactivation is a relatively common cause of morbidity following autologous hematopoietic cell transplant (auto-HCT). The Centers for Disease Control in 2009 recommended extending VZV prophylaxis for 1 year post-transplantation. We retrospectively analyzed rates of VZV
PMID 24097085

Calcium hydroxylapatite associated soft tissue necrosis: A case report and treatment guideline.

Tracy L1, Ridgway J2, Nelson JS3, Lowe N4, Wong B5.Author information 1Department of Otolaryngology - Head and Neck Surgery, University of California Irvine, 101 The City Drive, Bldg. 56, Suite 500, Orange, CA 92868, USA. Electronic address: ltracy@uci.edu.2Larrabee Center for Plastic Surgery, 600 Broadway, Suite 280, Seattle, WA 98122, USA.3Beckman Laser Institute and Medical Clinic, University of California Irvine, 1002 Health Sciences Road East, Irvine, CA 92612, USA.4999 North Tustin Avenue, Suite 117, Santa Ana, CA 92705, USA.5Department of Otolaryngology - Head and Neck Surgery, University of California Irvine, 101 The City Drive, Bldg. 56, Suite 500, Orange, CA 92868, USA; Beckman Laser Institute and Medical Clinic, University of California Irvine, 1002 Health Sciences Road East, Irvine, CA 92612, USA.AbstractWe present an uncommon case of nasal alar and facial necrosis following calcium hydroxylapatite filler injection performed elsewhere without direct physician supervision. The patient developed severe full-thickness necrosis of cheek and nasal alar skin 24 h after injections into the melolabial folds. Management prior to referral included oral antibiotics, prednisone taper, and referral to a dermatologist (day 3) who prescribed valacyclovir for a presumptive herpes zoster reactivation induced by the injection. Referral to our institution was made on day 11, and after herpetic outbreak was ruled out by a negative Tzanck smear, debridement with aggressive local wound care was initiated. After re-epithelialization and the fashioning of a custom intranasal stent to prevent vestibular stenosis, pulsed dye laser therapy was performed for wound modification. The patient healed with an acceptable cosmetic outcome. This report underscores the importance of facial vasculature anatomy, injection techniques, and identification of adverse events when using fillers. A current treatment paradigm for such events is also presented.
Journal of plastic, reconstructive & aesthetic surgery : JPRAS.J Plast Reconstr Aesthet Surg.2014 Apr;67(4):564-8. doi: 10.1016/j.bjps.2013.08.008. Epub 2013 Aug 28.
We present an uncommon case of nasal alar and facial necrosis following calcium hydroxylapatite filler injection performed elsewhere without direct physician supervision. The patient developed severe full-thickness necrosis of cheek and nasal alar skin 24 h after injections into the melolabial fold
PMID 23993752

Valacyclovir therapy does not reverse herpes-associated alterations in cervical immunology: a randomized, placebo-controlled crossover trial.

Yi TJ1, Shannon B, Chieza L, Su D, Saunders M, Tharao W, Huibner S, Remis R, Raboud J, Kaul R.Author information 1Departments of Medicine (TJY, BS, SH, RK), and Immunology (TJY, BS, RK), University of Toronto, Toronto, Ontario, Canada.AbstractHerpes simplex virus-2 (HSV-2) infection is associated with a three-fold increase in HIV acquisition risk, perhaps through alterations in mucosal HIV-susceptible target cells. We performed a clinical trial to assess the impact of herpes therapy on cervical immunology in HSV-2-infected, HIV-uninfected African/Caribbean women. Thirty participants were administered 1 g oral valacyclovir daily for 2 months in a randomized double-blind, placebo-controlled cross-over trial [#NCT00946556]. Valacyclovir did not reduce cervical CD4+ T cells, dendritic cells or pro-inflammatory cytokines, and tended to increase expression of the HIV co-receptor CCR5 and activation marker CD69. Short-term valacyclovir therapy did not reverse HSV-2-associated alterations in genital immunology.
The Journal of infectious diseases.J Infect Dis.2014 Mar 23. [Epub ahead of print]
Herpes simplex virus-2 (HSV-2) infection is associated with a three-fold increase in HIV acquisition risk, perhaps through alterations in mucosal HIV-susceptible target cells. We performed a clinical trial to assess the impact of herpes therapy on cervical immunology in HSV-2-infected, HIV-uninfecte
PMID 24664172

Japanese Journal

突発性難聴症例に対するバラシクロビル追加投与の効果について

牧野寛之,佐野肇,上條貴裕,岡本牧人
Otology Japan 20(5), 717-720, 2010-12-25
突発性難聴は未だ原因不明の疾患であるが、推測される病因の一つにヘルペスウィルスの再活性化が挙げられている。そのため治療に抗ウィルス薬を用いる試みがなされてきたが、これまでその効果を検討した報告の多くは聴力の改善において有意差を認めていない。今回我々はヘルペスウィルスの抗体価が高いものは再活性化と関連している可能性が高いと考え、2007年以降当院を初診した突発性難聴患者に血液検査を施行した。そして単 …
NAID 10027852180

症例塩酸バラシクロビルによる蕁麻疹型薬疹の1例

大野健太郎,池村志麻乃,田村真吾
皮膚科の臨床 52(1), 97-100, 2010-01
NAID 40016954387

Crystal Nephropathy Induced by Valaciclovir

Watanabe Maho,Saito Takao
福岡大学医学紀要 36(1), 93-95, 2009-03
NAID 110007014270

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★リンクテーブル★

リンク元	「バラシクロビル」
拡張検索	「valaciclovir hydrochloride」

「バラシクロビル」

Valaciclovir
Systematic (IUPAC) name
	(S)-2-[(2-amino-6-oxo-6,9-dihydro-3H-purin-9-yl)methoxy]ethyl-2-amino-3-methylbutanoate
Clinical data
Trade names	Valtrex
AHFS/Drugs.com	monograph
MedlinePlus	a695010
Licence data	US FDA:link
Pregnancy; category	AU: B3; US: B (No risk in non-human studies); ;
Legal status	AU: S4 (Prescription only); UK: POM (Prescription only); US: ℞-only; ℞ (Prescription only);
Routes of; administration	Oral
Pharmacokinetic data
Bioavailability	55%
Protein binding	13–18%
Metabolism	Hepatic (to aciclovir)
Biological half-life	<30 minutes (valaciclovir);; 2.5–3.6 hours (aciclovir)
Excretion	Renal 40–50% (aciclovir),; faecal 47% (aciclovir)
Identifiers
CAS Number	124832-26-4
ATC code	J05AB11
PubChem	CID 60773
IUPHAR/BPS	4824
DrugBank	DB00577
ChemSpider	54770
UNII	MZ1IW7Q79D
KEGG	D00398
ChEBI	CHEBI:35854
ChEMBL	CHEMBL1349
NIAID ChemDB	070982
Chemical data
Formula	C13H20N6O4
Molar mass	324.336 g/mol
	SMILES O=C(OCCOCn1c2N\C(=N/C(=O)c2nc1)N)[C@@H](N)C(C)C ;
	InChI InChI=1S/C13H20N6O4/c1-7(2)8(14)12(21)23-4-3-22-6-19-5-16-9-10(19)17-13(15)18-11(9)20/h5,7-8H,3-4,6,14H2,1-2H3,(H3,15,17,18,20)/t8-/m0/s1 ; Key:HDOVUKNUBWVHOX-QMMMGPOBSA-N ;
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　　[★]

英: valacyclovir、valaciclovir
化: 塩酸バラシクロビル, valaciclovir hydrochloride
商: バルトレックス
関: 抗ウイルス薬

適応

単純疱疹、帯状疱疹、性器ヘルペスの再発抑制、(水痘)

「valaciclovir hydrochloride」

　　[★] バラシクロビル。塩酸バラシクロビル

[1] Ahmed, Rumman (November 27, 2009). "Ranbaxy Launches Generic Valtrex in U.S.". The Wall Street Journal. Retrieved January 16, 2010.

[2] ttp://www.uscnk.us/protein-antibody-elisa/Valaciclovir-%28VCV%29-V511.htm

[OBrien1989-3] 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. PMID 2653790.

[balfour2005-4] Balfour et al. (December 2005) A controlled trial of valacyclovir in infectious mononucleosis. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC., December 18, 2005. Abstract V1392

[simon2003-5] Simon, Michael W.; Robert G. Deeter; Britt Shahan (March 2003). "The Effect of Valacyclovir and Prednisolone in Reducing Symptoms of EBV Illness In Children: A Double-Blind, Placebo-Controlled Study" (PDF). International Pediatrics 18 (3): 164–169. ^{[dead link]}

[pmid17369082-6] Balfour HH, Hokanson KM, Schacherer RM, et al. (May 2007). "A virologic pilot study of valacyclovir in infectious mononucleosis". Journal of Clinical Virology 39 (1): 16–21. doi:10.1016/j.jcv.2007.02.002. PMID 17369082.

[Martindale34-7] Sweetman, Sean C., ed. (2005). Martindale: the complete drug reference (34th ed.). London: Pharmaceutical Press. ISBN 0-85369-550-4. OCLC 56903116. ^{[page needed]}

[8] "B Virus—First Aid and Treatment—Herpes B—CDC". Retrieved June 6, 2015.

[9] "Valtrex Prescribing Information" (PDF). GlaxoSmithKline. September 2008. Retrieved May 7, 2009.

[AMH2006-10] Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3^{[page needed]}

[11] Lille, H. Martina; Wassilew, Sawko W. (2006). "Antiviral therapies of shingles in dermatology". In Gross, Gerd; Doerr, H.W. Herpes zoroster: recent aspects of diagnosis and control. Monographs in virology 26. Basel (Switzerland): Karger Publishers. p. 124. ISBN 978-3-8055-7982-7. Retrieved January 1, 2012.

[Cancer-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.

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valaciclovir