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{{Short description|Chemical compound}} |
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{{Unreferenced stub|auto=yes|date=December 2009}} |
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{{Drugbox |
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{{Drugbox |
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| Verifiedfields = changed |
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| Watchedfields = changed |
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| verifiedrevid = 399694997 |
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| verifiedrevid = 459982797 |
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| IUPAC_name = 5--1--1,2,3,4-tetrahydropyrimidine-2,4-dione |
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| IUPAC_name = 5--1--1,2,3,4-tetrahydropyrimidine-2,4-dione |
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| image = Brivudine - Brivudin.svg |
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| image = Brivudine - Brivudin.svg |
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<!--Clinical data--> |
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<!--Clinical data--> |
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| tradename = |
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| tradename = Zostex, Mevir, Brivir, many others |
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| Drugs.com = {{drugs.com|international|brivudine}} |
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| Drugs.com = {{drugs.com|international|brivudine}} |
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| pregnancy_category = exclusion |
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| pregnancy_category = Contraindicated |
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| legal_status = |
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| legal_status = Rx-only |
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| routes_of_administration = oral |
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| routes_of_administration = Oral |
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<!--Pharmacokinetic data--> |
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<!--Pharmacokinetic data--> |
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| bioavailability = 30% |
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| bioavailability = 30% |
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| protein_bound = >95% |
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| metabolism = |
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| metabolism = ] |
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| metabolites = Bromovinyluracil |
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| onset = |
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| elimination_half-life = 16 hours |
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| elimination_half-life = 16 hours |
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| duration_of_action = |
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| excretion = mainly renal |
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| excretion = 65% ] (mainly metabolites), 20% ] |
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<!--Identifiers--> |
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<!--Identifiers--> |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number_Ref = {{cascite|changed|??}} |
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| CAS_number = <!-- blanked - oldvalue: 69304-47-8 --> |
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| CAS_number = 69304-47-8 |
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| ATC_prefix = J05 |
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| ATC_prefix = J05 |
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| ATC_suffix = AB15 |
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| ATC_suffix = AB15 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 394011 |
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| ChemSpiderID = 394011 |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = 2M3055079H |
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| UNII = 2M3055079H |
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| ChEMBL_Ref = {{ebicite|changed|EBI}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 31634 |
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| ChEMBL = 31634 |
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| KEGG_Ref = {{keggcite|changed|kegg}} |
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| KEGG = D07249 |
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| synonyms = BVDU |
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<!--Chemical data--> |
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<!--Chemical data--> |
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| C=11 | H=13 | Br=1 | N=2 | O=5 |
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| C=11 | H=13 | Br=1 | N=2 | O=5 |
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| molecular_weight = 333.135 g/mol |
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| smiles = Br=CC=1C(=O)NC(=O)N(C=1)2O((O)C2)CO |
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| smiles = Br=CC=1C(=O)NC(=O)N(C=1)2O((O)C2)CO |
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| InChI = 1/C11H13BrN2O5/c12-2-1-6-4-14(11(18)13-10(6)17)9-3-7(16)8(5-15)19-9/h1-2,4,7-9,15-16H,3,5H2,(H,13,17,18)/b2-1+/t7-,8+,9+/m0/s1 |
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| InChIKey = ODZBBRURCPAEIQ-PIXDULNEBW |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C11H13BrN2O5/c12-2-1-6-4-14(11(18)13-10(6)17)9-3-7(16)8(5-15)19-9/h1-2,4,7-9,15-16H,3,5H2,(H,13,17,18)/b2-1+/t7-,8+,9+/m0/s1 |
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| StdInChI = 1S/C11H13BrN2O5/c12-2-1-6-4-14(11(18)13-10(6)17)9-3-7(16)8(5-15)19-9/h1-2,4,7-9,15-16H,3,5H2,(H,13,17,18)/b2-1+/t7-,8+,9+/m0/s1 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = ODZBBRURCPAEIQ-PIXDULNESA-N |
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| StdInChIKey = ODZBBRURCPAEIQ-PIXDULNESA-N |
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| density = 1.86 |
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| melting_point = 165 |
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| melting_high = 166 |
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| melting_notes = (decomposes) |
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| specific_rotation = +9°±1° |
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}} |
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}} |
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'''Brivudine''' is an ] used in the treatment of ]. |
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'''Brivudine''' (trade names '''Zostex''', '''Mevir''', '''Brivir''', among others) is an ] used in the treatment of ] ("shingles"). Like other antivirals, it acts by inhibiting ] of the target virus. |
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==Medical uses== |
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Brivudine is used for the treatment of herpes zoster in adult patients. It is taken orally once daily, in contrast to ], ] and other antivirals.<ref name="Austria-Codex" /> A study has found that it is more effective than ], but this has been disputed because of a possible ] on part of the study authors.<ref name="at" /> |
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==Contraindications== |
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The drug is contraindicated in patients undergoing ] (for example because of an ]) or cancer therapy, especially with ] (5-FU) and chemically related ] such as ] and ], as well as the ] drug ], which is also related to 5-FU. It has not been proven to be safe in children and pregnant or breastfeeding women.<ref name="Austria-Codex" /> |
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==Adverse effects== |
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The drug is generally well tolerated. The only common side effect is ] (in 2% of patients). Less common side effects (<1%) include headache, increased or lowered blood cell counts (], ], ], ]), increased liver enzymes, and allergic reactions.<ref name="Austria-Codex" /> |
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== Interactions == |
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Brivudine interacts strongly and in rare cases lethally with the anticancer drug ] (5-FU), its prodrugs and related substances. Even ] applied 5-FU can be dangerous in combination with brivudine. This is caused by the main ], bromovinyluracil (BVU), irreversibly inhibiting the enzyme ] (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 ] which also has BVU as its main metabolite.<ref name="Austria-Codex" /><ref name="DÄB" /> |
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There are no other relevant interactions. Brivudine does not significantly influence the ] enzymes in the liver.<ref name="Austria-Codex" /> |
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==Pharmacology== |
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===Spectrum of activity=== |
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The drug inhibits ] of ] (VZV) – which causes herpes zoster – and ] type 1 (HSV-1), but not HSV-2 which typically causes genital herpes. '']'', ]s against VZV are 200- to 1000-fold lower than those of aciclovir and ], theoretically indicating a much higher potency of brivudine. Clinically relevant VZV strains are particularly sensitive.<ref name="Steinhilber" /> |
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===Mechanism of action=== |
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Brivudine is an analogue of the ] ]. The active compound is brivudine 5'-triphosphate, which is formed in subsequent ]s by viral (but not human) ] and presumably by ]. Brivudine 5'-triphosphate works because it is incorporated into the viral DNA, but then blocks the action of ], thus inhibiting viral replication.<ref name="Austria-Codex" /><ref name="Steinhilber" /> |
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===Pharmacokinetics=== |
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Brivudine is well and rapidly absorbed from the gut and undergoes ] in the liver, where the enzyme ]<ref>{{cite journal | vauthors = Desgranges C, Razaka G, Rabaud M, Bricaud H, Balzarini J, De Clercq E | title = Phosphorolysis of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and other 5-substituted-2'-deoxyuridines by purified human thymidine phosphorylase and intact blood platelets | journal = Biochemical Pharmacology | volume = 32 | issue = 23 | pages = 3583–90 | date = December 1983 | pmid = 6651877 | doi = 10.1016/0006-2952(83)90307-6 }}</ref> quickly splits off the sugar component, leading to a ] 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.<ref name="Austria-Codex" /><ref name="Mutschler" /> |
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Highest blood plasma concentrations are reached after one hour. Brivudine is almost completely (>95%) ]. ] is 16 hours; 65% of the substance are found in the urine and 20% in the faeces, mainly in form of an ] derivative (which is not detectable in the plasma), but also other water-soluble metabolites, which are ] derivatives. Less than 1% is excreted in form of the original compound.<ref name="Austria-Codex" /> |
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<gallery mode=packed> |
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File:Brivudine triphosphate.svg|Brivudine 5'-triphosphate, the ] |
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File:Bromovinyluracil skeletal.svg|Bromovinyluracil (BVU), the main inactive metabolite |
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File:Uracil acetic acid.svg|The ] derivative predominantly found in urine |
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</gallery> |
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==Chemistry== |
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The molecule has three ] carbon atoms in the ] (sugar) part all of which have defined orientation; i.e. the drug is ]ly pure.<ref name="Austria-Codex" /> The substance is a white powder. |
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==Manufacturing== |
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Main supplier is ], now part of Italy's ] Group. In Central America is provided by Menarini Centro America and Wyeth.{{citation needed|date=February 2016}} |
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==History== |
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==History== |
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Brivudine is a similar drug to ]{{Clarify|date=July 2009}}. The compound was first synthesized by scientists at the ] in the UK in the 1970s. It was shown to be a potent inhibitor of the ] Type 1 (HSV-1) as well as the ] (VZV) by Erik De Clercq at the ] in ] in 1979. In the 1980s the drug became commercially available in ], where it was marketed as '''Helpin''' by a pharmaceutical company called Berlin-Chemie. |
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The substance was first synthesized by scientists at the ] in the UK in 1976. It was shown to be a potent inhibitor of HSV-1 and VZV by ] at the ] in ] in 1979. In the 1980s the drug became commercially available in ], 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.<ref name="DeClerq" /><ref name="bioactive" /> |
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Brivudine is approved for use in a number of European countries including Austria, Belgium, Germany, Greece, Italy, Portugal, Spain and Switzerland.<ref name="International">{{cite web | url = https://www.drugs.com/international/brivudine.html | title = Brivudine | work = drugs.com }}</ref> |
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==Approvals== |
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Brivudine is approved for use in ] and other ]an countries including ]. |
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==Etymology== |
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==Mechanism of Action== |
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The name ''brivudine'' derives from the chemical nomenclature '']-]-]'' or BVDU for short. It is sold under trade names such as Bridic, Brival, Brivex, Brivir, Brivirac, Brivox, Brivuzost, Zerpex, Zonavir, Zostex, and Zovudex.<ref name="International" /> |
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Brivudine is an analogue of the ] ]. The drug works because it is able to be incorporated into the viral DNA, but then blocks the action of DNA ], thus inhibiting viral replication. The active compound is the 5'-triphosphate of BVDU, which is formed in subsequent phosphorylations by viral thymidine kinase and presumably by nucleoside diphosphate kinase. |
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==The drug's name== |
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==Research== |
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A ] examined the effectiveness of multiple antiviral drugs in the treatment of ]. Brivudine was found to be significantly more effective than ] in increasing the number of successfully healed eyes of participants.<ref name="Wilhelmus2015" /> |
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Brivudine derives from the drug's chemical name of bromovinyldeoxyuridine or BVDU for short. The drug's full chemical description is (E)-5-(2-bromovinyl)-2-deoxyuridine. It is also sold as Bridic, Brivox, Brivudin, Helpin, Zerpex, Zonavir and Zostex. |
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==Suppliers== |
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== See also == |
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'''Related antiviral drugs''' |
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Brivudine main supplier is Berlin-Chemie, now part of Italy's Menarini Group. The drug is approved for sale in Austria, Belgium, Germany, Greece, Italy, Luxembourg, Portugal and Spain. In Central America is provided Meranini Centro America and Wyeth. |
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* ] |
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* ], a prodrug form of aciclovir |
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* ], an analogue of Penciclovir with greater oral availability |
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* ], an intravenous antiviral for aciclovir-resistant VZV |
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* ], a topical preparation |
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'''Vaccines and other treatments''' |
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{{Antivirals}} |
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* ], a live virus Herpes zoster (shingles) vaccine |
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* ], a live virus Varicella Zoster (chickenpox) vaccine |
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* ], a recombinant subunit vaccine for shingles |
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* ], an antibody-based treatment for immune-suppressed patients with zoster |
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== References == |
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] |
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{{reflist|35em|refs= |
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<ref name="Wilhelmus2015">{{cite journal | vauthors = Wilhelmus KR | title = Antiviral treatment and other therapeutic interventions for herpes simplex virus epithelial keratitis | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD002898 | date = January 2015 | issue = 1 | pmid = 25879115 | pmc = 4443501 | doi = 10.1002/14651858.CD002898.pub5 }}</ref> |
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<ref name="Austria-Codex">{{cite book|title=Austria-Codex| veditors = Jasek W |publisher=Österreichischer Apothekerverlag|location=Vienna|year=2007|edition=62nd|isbn=978-3-85200-181-4|pages=5246–8|language=German}}</ref> |
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{{Antimicrobial-stub}} |
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<ref name="Steinhilber">{{cite book|title=Medizinische Chemie| vauthors = Steinhilber D, Schubert-Zsilavecz M, Roth HJ|publisher=Deutscher Apotheker Verlag|location=Stuttgart|year=2005|isbn=3-7692-3483-9|pages=581–2|language=German}}</ref> |
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<ref name="Mutschler">{{Cite book| vauthors = Mutschler E, Schäfer-Korting M |title= Arzneimittelwirkungen |language=German |location=Stuttgart|publisher=Wissenschaftliche Verlagsgesellschaft|year=2001|edition=8|page=847|isbn=3-8047-1763-2}}</ref> |
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<ref name="at">{{cite journal|url=http://www.arznei-telegramm.de/html/2007_05/0705047_01.html|journal=Arznei-telegramm|volume=5/2007|title=Brivudin (Zostex) besser als Aciclovir (Zovirax a.a.)?|language=de}}</ref> |
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<ref name="DÄB">{{cite journal|url=http://www.akdae.de/Arzneimittelsicherheit/Bekanntgaben/Archiv/2006/764-200607071.pdf|title=UAW – Aus Fehlern lernen - Potenziell tödlich verlaufende Wechselwirkung zwischen Brivudin (Zostex) und 5-Fluoropyrimidinen|journal=Deutsches Ärzteblatt|volume=103|issue=27|date=7 July 2006|language=de}}</ref> |
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<ref name="DeClerq">{{cite journal | vauthors = De Clercq E | title = Discovery and development of BVDU (brivudin) as a therapeutic for the treatment of herpes zoster | journal = Biochemical Pharmacology | volume = 68 | issue = 12 | pages = 2301–15 | date = December 2004 | pmid = 15548377 | doi = 10.1016/j.bcp.2004.07.039 }}</ref> |
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<ref name="bioactive">{{cite book|title=Bioactive Compounds from Natural Sources|url=https://archive.org/details/bioactivecompoun00trin_854|url-access=limited| veditors = Tringali C |publisher=CRC Press |year=2012 |edition=2nd |page= }}</ref> |
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}} |
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{{Antivirals}} |
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] |
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] |
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] |
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] |