Valaciclovir, also spelled valacyclovir, is an

antiviral medication Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do ...

used to treat outbreaks of

herpes simplex Herpes simplex is a viral infection caused by the herpes simplex virus. Infections are categorized based on the part of the body infected. Oral herpes involves the face or mouth. It may result in small blisters in groups often called col ...

herpes zoster Shingles, also known as zoster or herpes zoster, is a viral disease characterized by a painful skin rash with blisters in a localized area. Typically the rash occurs in a single, wide mark either on the left or right side of the body or face. ...

(shingles). It is also used to prevent cytomegalovirus following a

kidney transplant Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantati ...

in high risk cases. It is taken by mouth. Common side effects include headache and

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteri ...

. Severe side effects may include

kidney problems Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

. Use in

pregnancy Pregnancy is the time during which one or more offspring develops (gestation, gestates) inside a woman, woman's uterus (womb). A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occur ...

appears to be safe. It is a prodrug, which works after being converted to

aciclovir Aciclovir (ACV), also known as acyclovir, is an antiviral medication. It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles. Other uses include prevention of cytomegalovirus infections following tra ...

in a person's body. Valaciclovir was patented in 1987 and came into medical use in 1995. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. It is available as a generic medication. In 2020, it was the 119th most commonly prescribed medication in the United States, with more than 5million prescriptions.

Medical uses

Valaciclovir is used for the treatment of HSV and VZV infections, including:Rossi S, editor.

Australian Medicines Handbook Australian Medicines Handbook (AMH) is a peer-reviewed medicines prescribing guide for Australian health professionals. The handbook is available in paper and digital formats and is supplemented by the ''AMH Aged Care Companion'' and the ''AMH C ...

2006. Adelaide: Australian Medicines Handbook; 2006. * Oral and genital

(treatment and

prevention Prevention may refer to: Health and medicine * Preventive healthcare, measures to prevent diseases or injuries rather than curing them or treating their symptoms General safety * Crime prevention, the attempt to reduce deter crime and crim ...

) * Reduction of HSV transmission from people with recurrent infection to uninfected individuals *

Herpes zoster Shingles, also known as zoster or herpes zoster, is a viral disease characterized by a painful skin rash with blisters in a localized area. Typically the rash occurs in a single, wide mark either on the left or right side of the body or face. ...

(shingles): the typical dosage for treatment of herpes is 1,000 mg orally three times a day for seven consecutive days. * Prevention of cytomegalovirus following

organ transplantation Organ transplantation is a medical procedure in which an organ is removed from one body and placed in the body of a recipient, to replace a damaged or missing organ. The donor and recipient may be at the same location, or organs may be transpor ...

* Prevention of herpesviruses in immunocompromised people (such as those undergoing cancer chemotherapy) * Chickenpox in children (ages 2–18) It has shown promise as a treatment for

infectious mononucleosis Infectious mononucleosis (IM, mono), also known as glandular fever, is an infection usually caused by the Epstein–Barr virus (EBV). Most people are infected by the virus as children, when the disease produces few or no symptoms. In young adult ...

and is preventively administered in suspected cases of herpes B virus exposure. Bell's palsy does not seem to benefit from using valaciclovir as its only treatment.

Adverse effects

Common

adverse drug reaction An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. The meaning of this term ...

s (≥1% of people) associated with valaciclovir are the same as for

, its active metabolite. They include: nausea, vomiting, diarrhea and headache. Infrequent adverse effects (0.1–1% of patients) include: agitation,

vertigo Vertigo is a condition where a person has the sensation of movement or of surrounding objects moving when they are not. Often it feels like a spinning or swaying movement. This may be associated with nausea, vomiting, sweating, or difficulties w ...

, confusion, dizziness, edema,

arthralgia Arthralgia (from Greek ''arthro-'', joint + ''-algos'', pain) literally means ''joint pain''. Specifically, arthralgia is a symptom of injury, infection, illness (in particular arthritis), or an allergic reaction to medication. According to MeSH, ...

, sore throat, constipation, abdominal pain, rash, weakness and/or

renal impairment Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...

. Rare adverse effects (<0.1% of patients) include: coma, seizures, neutropenia,

leukopenia Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of in ...

, tremor,

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

encephalopathy Encephalopathy (; from grc, ἐνκέφαλος "brain" + πάθος "suffering") means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but r ...

, psychotic symptoms,

crystalluria Crystalluria refers to crystals found in the urine when performing a urine test. Crystalluria is considered often as a benign condition and as one of the side effects of sulfonamides and penicillins. The main reason for the identification of urin ...

anorexia Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gre ...

, fatigue,

hepatitis Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes ( jaundice), poor appetite, vomiting, tiredness, abdominal ...

Stevens–Johnson syndrome Stevens–Johnson syndrome (SJS) is a type of severe skin reaction. Together with toxic epidermal necrolysis (TEN) and Stevens–Johnson/toxic epidermal necrolysis (SJS/TEN), it forms a spectrum of disease, with SJS being less severe. Erythema ...

toxic epidermal necrolysis Toxic epidermal necrolysis (TEN) is a type of severe skin reaction. Together with Stevens–Johnson syndrome (SJS) it forms a spectrum of disease, with TEN being more severe. Early symptoms include fever and flu-like symptoms. A few days later ...

and/or

anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the foll ...

Pharmacology

Valaciclovir is a prodrug, an

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides a ...

ified version of

that has greater oral bioavailability (about 55%) than aciclovir. It is converted by

esterase An esterase is a hydrolase enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis. A wide range of different esterases exist that differ in their substrate specificity, their protein structure ...

s to the active drug,

, and the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotona ...

via

hepatic The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it is ...

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the system ...

Aciclovir Aciclovir (ACV), also known as acyclovir, is an antiviral medication. It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles. Other uses include prevention of cytomegalovirus infections following tra ...

is selectively converted into a monophosphate form by viral

thymidine kinase Thymidine kinase is an enzyme, a phosphotransferase (a kinase): 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Cert ...

, which is more effective (3000 times) in phosphorylation of

than cellular thymidine kinase. Subsequently, the monophosphate form is further phosphorylated into a disphosphate by cellular guanylate kinase and then into the active triphosphate form, aciclo- GTP, by cellular kinases.

Mechanism of action

Aciclo-GTP, the active triphosphate metabolite of aciclovir, is a very potent inhibitor of viral

DNA replication In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...

. Aciclo-GTP competitively inhibits and inactivates the viral

DNA polymerase A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create ...

. Its monophosphate form also incorporates into the viral DNA, resulting in

chain termination Chain termination is any chemical reaction that ceases the formation of reactive intermediates in a chain propagation step in the course of a polymerization, effectively bringing it to a halt. Mechanisms of termination In polymer chemistry, ...

. It has also been shown that the viral enzymes cannot remove aciclo-

GMP GMP may refer to: Finance and economics * Gross metropolitan product * Guaranteed maximum price * Guaranteed Minimum Pension Science and technology * GNU Multiple Precision Arithmetic Library, a software library * Granulocyte-macrophage progenito ...

from the chain, which results in inhibition of further activity of DNA polymerase. Aciclo-GTP is fairly rapidly metabolized within the cell, possibly by cellular phosphatases. Aciclovir is active against most species in the

herpesvirus ''Herpesviridae'' is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word ''ἕρπειν ...

family. In descending order of activity: * Herpes simplex virus type I (HSV-1) * Herpes simplex virus type II (HSV-2) *

Varicella zoster virus Varicella-zoster virus (VZV), also known as human herpesvirus 3 (HHV-3, HHV3) or ''Human alphaherpesvirus 3'' (taxonomically), is one of nine known herpes viruses that can infect humans. It causes chickenpox (varicella) commonly affecting chil ...

(VZV) *

Epstein–Barr virus The Epstein–Barr virus (EBV), formally called ''Human gammaherpesvirus 4'', is one of the nine known human herpesvirus types in the herpes family, and is one of the most common viruses in humans. EBV is a double-stranded DNA virus. It is b ...

(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, valaciclovir has 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.Balfour ''et al.'' (December 2005) A controlled trial of valaciclovir in infectious mononucleosis. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, DC., 18 December 2005. Abstract V1392 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 effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s. Acyclovir therapy does prevent viral latency, but has not proven effective at eradicating latent viruses in nerve ganglia. As of 2005, resistance to valaciclovir has not been significant. Mechanisms of resistance in HSV include deficient viral thymidine kinase and mutations to viral thymidine kinase and/or DNA polymerase that alter substrate sensitivity. It also is used for herpes B virus postexposure prophylaxis.

Chemistry

Details of the synthesis of valaciclovir were first published by scientists from the

Wellcome Foundation The Wellcome Trust is a charitable foundation focused on health research based in London, in the United Kingdom. It was established in 1936 with legacies from the pharmaceutical magnate Henry Wellcome (founder of one of the predecessors of Glax ...

. :

Aciclovir was esterified with a

carboxybenzyl Benzyl chloroformate, also known as benzyl chlorocarbonate or Z-chloride, is the benzyl ester of chloroformic acid. It can be also described as the chloride of the benzyloxycarbonyl (Cbz or Z) group. In its pure form it is a water-sensitive oily c ...

protected Protection is any measure taken to guard a thing against damage caused by outside forces. Protection can be provided to physical objects, including organisms, to systems, and to intangible things like civil and political rights. Although th ...

, using

dicyclohexylcarbodiimide ''N'',''N''′-Dicyclohexylcarbodiimide (DCC or DCCD) is an organic compound with the chemical formula (C6H11N)2C. It is a waxy white solid with a sweet odor. Its primary use is to couple amino acids during artificial peptide synthesis. The low ...

as the dehydrating agent. In the final step, the protecting group was removed by

hydrogenation Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to reduce or saturate organ ...

using a palladium on alumina catalyst.

History

Valaciclovir was patented in 1987 and came into medical use in 1995. It is available as a generic medication. In 2019, it was the 110th most commonly prescribed medication in the United States, with more than 5million prescriptions.

Society and culture

Brand names

It is marketed by GlaxoSmithKline under the brand names Valtrex and Zelitrex. Valaciclovir has been available as a generic drug in the U.S. since November 2009.

References

External links

* * {{Portal bar , Medicine Amino acid derivatives Anti-herpes virus drugs GSK plc brands Carboxylate esters Ethers Prodrugs Purines Herpes World Health Organization essential medicines Wikipedia medicine articles ready to translate