Brivudine (trade names Zostex, Mevir, Brivir, among others) is an

antiviral drug 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 n ...

used in the treatment of

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"). Like other antivirals, it acts by inhibiting replication of the target virus.

Medical uses

Brivudine is used for the treatment of herpes zoster in adult patients. It is taken orally once daily, in contrast 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 tran ...

valaciclovir Valaciclovir, also spelled valacyclovir, is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster (shingles). It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases. It is taken ...

and other antivirals. A study has found that it is more effective than

, but this has been disputed because of a possible

conflict of interest A conflict of interest (COI) is a situation in which a person or organization is involved in multiple interests, financial or otherwise, and serving one interest could involve working against another. Typically, this relates to situations i ...

on part of the study authors.

Contraindications

The drug is contraindicated in patients undergoing

immunosuppression Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse react ...

(for example because of an

organ transplant 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 transpo ...

) or cancer therapy, especially with

fluorouracil Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancreat ...

(5-FU) and chemically related (pro)drugs such as

capecitabine Capecitabine, sold under the brand name Xeloda among others, is a chemotherapy medication used to treat breast cancer, gastric cancer and colorectal cancer. For breast cancer it is often used together with docetaxel. It is taken by mouth. Comm ...

and

tegafur Tegafur is a chemotherapeutic prodrug of 5-fluorouracil (5-FU) used in the treatment of cancers. It is a component of the combination drug tegafur/uracil. When metabolised, it becomes 5-FU. It was patented in 1967 and approved for medical use in ...

, as well as the

antimycotic An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as crypto ...

drug

flucytosine Flucytosine, also known as 5-fluorocytosine (5-FC), is an antifungal medication. It is specifically used, together with amphotericin B, for serious ''Candida'' infections and cryptococcosis. It may be used by itself or with other antifungals for ...

, which is also related to 5-FU. It has not been proven to be safe in children and pregnant or breastfeeding women.

Adverse effects

The drug is generally well tolerated. The only common side effect is

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

(in 2% of patients). Less common side effects (<1%) include headache, increased or lowered blood cell counts (

granulocytopenia Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They hav ...

anaemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...

lymphocytosis Lymphocytosis is an increase in the number or proportion of lymphocytes in the blood. Absolute lymphocytosis is the condition where there is an increase in the lymphocyte count beyond the normal range while relative lymphocytosis refers to the cond ...

monocytosis Monocytosis is an increase in the number of monocytes circulating in the blood. Monocytes are white blood cells that give rise to macrophages and dendritic cells in the immune system. In humans, monocytosis occurs when there is a sustained rise i ...

), increased liver enzymes, and allergic reactions.

Interactions

Brivudine interacts strongly and in rare cases lethally with the anticancer drug

(5-FU), its prodrugs and related substances. Even

topically A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes ...

applied 5-FU can be dangerous in combination with brivudine. This is caused by the main

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

, bromovinyluracil (BVU), irreversibly inhibiting the enzyme

dihydropyrimidine dehydrogenase In enzymology, a dihydropyrimidine dehydrogenase (NADP+) () is an enzyme that catalyzes the chemical reaction :5,6-dihydrouracil + NADP+ \rightleftharpoons uracil + NADPH + H+ Thus, the two substrates of this enzyme are 5,6-dihydrouracil and ...

(DPD) which is necessary for inactivating 5-FU. After a standard brivudine therapy, DPD function can be compromised for up to 18 days. This interaction is shared with the closely related drug

sorivudine Sorivudine (INN), is a nucleoside analogue antiviral drug, marketed under trade names such as Usevir ( Nippon Shoji, Eisai) and Brovavir (BMS). It is used for the treatment of varicella zoster virus infections. Pharmacology Feature * First-line ...

which also has BVU as its main metabolite. There are no other relevant interactions. Brivudine does not significantly influence the

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

enzymes in the liver.

Pharmacology

Spectrum of activity

The drug inhibits replication of

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) – which causes herpes zoster – and

herpes simplex virus Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and '' Human alphaherpesvirus 2'', are two members of the human ''Herpesviridae'' family, a set of viruses that produce viral inf ...

type 1 (HSV-1), but not HSV-2 which typically causes genital herpes. ''

In vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

'', inhibitory concentrations against VZV are 200- to 1000-fold lower than those of aciclovir and

penciclovir Penciclovir is a guanosine analogue antiviral drug used for the treatment of various herpesvirus infections. It is a nucleoside analogue which exhibits low toxicity and good selectivity. Because penciclovir is absorbed poorly when given orally (b ...

, theoretically indicating a much higher potency of brivudine. Clinically relevant VZV strains are particularly sensitive.

Mechanism of action

Brivudine is an analogue of the

nucleoside Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose) whereas a nucleotide ...

thymidine Thymidine (symbol dT or dThd), also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine (A) in double-stranded DNA. I ...

. The active compound is brivudine 5'-triphosphate, which is formed in subsequent

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

s by viral (but not human)

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 ...

and presumably by

nucleoside-diphosphate kinase Nucleoside-diphosphate kinases (NDPKs, also NDP kinase, (poly)nucleotide kinases and nucleoside diphosphokinases) are enzymes that catalyze the exchange of terminal phosphate between different nucleoside diphosphates (NDP) and triphosphates (NTP) ...

. Brivudine 5'-triphosphate works because it is incorporated into the viral DNA, but then blocks the action of

DNA polymerases 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 ...

, thus inhibiting viral replication.

Pharmacokinetics

Brivudine is well and rapidly absorbed from the gut and undergoes

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 systemi ...

in the liver, where the enzyme

thymidine phosphorylase Thymidine phosphorylase () is an enzyme that is encoded by the TYMP (gene), TYMP gene and catalyzes the reaction: :thymidine + phosphate \rightleftharpoons thymine + 2-deoxy-alpha-D-ribose 1-phosphate Thymidine phosphorylase is involved in purin ...

quickly splits off the sugar component, leading to a

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of 30%. The resulting metabolite is bromovinyluracil (BVU), which does not have antiviral activity. BVU is also the only metabolite that can be detected in the blood plasma. Highest blood plasma concentrations are reached after one hour. Brivudine is almost completely (>95%) bound to plasma proteins.

Terminal half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

is 16 hours; 65% of the substance are found in the urine and 20% in the faeces, mainly in form of an

acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main component ...

derivative (which is not detectable in the plasma), but also other water-soluble metabolites, which are

urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important r ...

derivatives. Less than 1% is excreted in form of the original compound. File:Brivudine triphosphate.svg, Brivudine 5'-triphosphate, the

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

File:Bromovinyluracil skeletal.svg, Bromovinyluracil (BVU), the main inactive metabolite File:Uracil acetic acid.svg, The

derivative predominantly found in urine

Chemistry

The molecule has three

chiral Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from ...

carbon atoms in the

deoxyribose Deoxyribose, or more precisely 2-deoxyribose, is a monosaccharide with idealized formula H−(C=O)−(CH2)−(CHOH)3−H. Its name indicates that it is a deoxy sugar, meaning that it is derived from the sugar ribose by loss of a hydroxy group. D ...

(sugar) part all of which have defined orientation; i.e. the drug is

stereochemical Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereois ...

ly pure. The substance is a white powder.

Manufacturing

Main supplier is

Berlin Chemie Berlin-Chemie AG is a German pharmaceutical company based in Berlin, Germany. It is part of the Menarini Group. History Berlin-Chemie considers the establishment of a plant for the laboratory preparations of the Chemical factory of Kahlbaum in ...

, now part of Italy's

Menarini The Menarini Group is an Italian pharmaceutical company. Its headquarters is in Florence, Tuscany, and it has three divisions: Menarini Ricerche, Menarini Biotech, and Menarini Diagnostics. It develops pharmacological solutions for cardiovascula ...

Group. In Central America is provided by Menarini Centro America and Wyeth.

History

The substance was first synthesized by scientists at the

University of Birmingham , mottoeng = Through efforts to heights , established = 1825 – Birmingham School of Medicine and Surgery1836 – Birmingham Royal School of Medicine and Surgery1843 – Queen's College1875 – Mason Science College1898 – Mason Univers ...

in the UK in 1976. It was shown to be a potent inhibitor of HSV-1 and VZV by Erik De Clercq at the

Rega Institute for Medical Research The Rega Institute for Medical Research is a Belgian scientific establishment that is part of the Catholic University of Leuven (Leuven) in central Belgium. The Rega Institute is an interfacultary biomedical research institute of the Catholic Univ ...

Belgium Belgium, ; french: Belgique ; german: Belgien officially the Kingdom of Belgium, is a country in Northwestern Europe. The country is bordered by the Netherlands to the north, Germany to the east, Luxembourg to the southeast, France to th ...

in 1979. In the 1980s the drug became commercially available in

East Germany East Germany, officially the German Democratic Republic (GDR; german: Deutsche Demokratische Republik, , DDR, ), was a country that existed from its creation on 7 October 1949 until its dissolution on 3 October 1990. In these years the state ...

, where it was marketed as ''Helpin'' by a pharmaceutical company called Berlin-Chemie. Only after the indication was changed to the treatment of herpes zoster in 2001 did it become more widely available in Europe. Brivudine is approved for use in a number of European countries including Austria, Belgium, Germany, Greece, Italy, Portugal, Spain and Switzerland.: Brivudine.

Etymology

The name ''brivudine'' derives from the chemical nomenclature '' bromo-

vinyl Vinyl may refer to: Chemistry * Polyvinyl chloride (PVC), a particular vinyl polymer * Vinyl cation, a type of carbocation * Vinyl group, a broad class of organic molecules in chemistry * Vinyl polymer, a group of polymers derived from vinyl m ...

deoxyuridine Deoxyuridine (dU) is a compound and a nucleoside.It belongs to a class of compounds known as Pyrimidine 2'-deoxyribonucleosides and closely resembles the chemical composition of uridine but without the presence of the 2' hydroxyl group. Idoxuridine ...

'' or BVDU for short. It is sold under trade names such as Bridic, Brival, Brivex, Brivir, Brivirac, Brivox, Brivuzost, Zerpex, Zonavir, Zostex, and Zovudex.

Research

A Cochrane Systematic Review examined the effectiveness of multiple antiviral drugs in the treatment of herpes simplex virus epithelial keratitis. Brivudine was found to be significantly more effective than

idoxuridine Idoxuridine is an anti-herpesvirus antiviral drug. It is a nucleoside analogue, a modified form of deoxyuridine, similar enough to be incorporated into viral DNA replication, but the iodine atom added to the uracil component blocks base pairing. I ...

in increasing the number of successfully healed eyes of participants.

References

{{Antivirals Nucleosides Pyrimidinediones Organobromides Anti-herpes virus drugs Hydroxymethyl compounds