Ribavirin
Encyclopedia
Ribavirin is an anti-viral drug indicated for severe RSV
infection (individually), hepatitis C infection (used in conjunction with peginterferon alfa-2b
or peginterferon alfa-2a) and other viral infections. Ribavirin is a prodrug
, which when metabolised resembles purine
RNA
nucleotide
s. In this form it interferes with RNA metabolism required for viral replication. How it exactly affects viral replication is unknown; many mechanisms have been proposed for this (see Mechanisms of Action, below) but none of these has been proven to date. Multiple mechanisms may be responsible for its actions.
The primary observed serious adverse side effect
of ribavirin is hemolytic anemia
, which may worsen preexisting cardiac disease. The mechanism for this effect is due to ribavarin's buildup inside erythrocytes. Oxidative damage to erythrocyte cell membrane is usually inhibited by glutathione
; however, with reduced ATP levels caused by ribavirin, glutathione levels are impaired, permitting oxidative erythrocyte cell lysis. The gradual loss of erythrocytes leads to anemia. The anemia is dose-dependent and may sometimes be compensated by decreasing dose. Ribavirin is also a teratogen
in some animals species and thus poses a theoretical reproductive risk in humans, remaining a hazard as long as the drug is present, which can be as long as 6 months after a course of the drug has ended.
and RNA
virus
es. It is a member of the nucleoside
antimetabolite drugs that interfere with duplication of viral genetic material. Ribavirin is active against influenza
s, flavivirus
es and agents of many viral hemorrhagic fever
s.
In Europe and the U.S. the oral (capsule or tablet) form of ribavirin is used in the treatment of hepatitis C
, in combination with pegylated
interferon
drugs.
Ribavirin is the only known treatment for a variety of viral hemorrhagic fever
s, including Lassa fever
, Crimean-Congo hemorrhagic fever
, and Hantavirus
infection, although data regarding these infections are scarce and the drug might be effective only in early stages.
The aerosol form has been used in the past to treat respiratory syncytial virus-related diseases in children. However, its efficacy has been called into question by multiple studies, and most institutions no longer use it. It is still used in some cases.
In Mexico, ribavirin ("ribavirina") has been sold for use against influenza
. Studies have been mixed, but the derivative viramidine
may have more promise.
It has been used (in combination with ketamine
, midazolam
, and amantadine
) in treatment of rabies
.
This drug is also used to control the life span of enterovirus 71 which causes hand, foot, and mouth disease.
, hepatitis B, polio, measles
, Canine distemper
and smallpox
. Ribavirin is active in a hamster model of yellow fever
, a finding which is not surprising, given the familial relationship of yellow fever
and hepatitis C
viruses as flaviviridae
. Ribavirin is active against other important flaviviridae
such as West Nile virus
and dengue fever
.
Ribavirin has also been used as a treatment for herpes simplex virus. One small study found that ribavirin treatment reduced the severity of herpes outbreaks and promoted recovery, as compared with placebo treatment. Another study found that ribavirin potentiated the antiviral effect of acyclovir.
Ribavirin's present generic status is expected to slow research into new uses, however.
with royalty payments for licensing made to Valeant Pharmaceuticals International
(see History below). It was also marketed as Copegus tablets by Roche Pharmaceuticals under a separate license to Valeant Pharmaceuticals International
. After concluding patent disputes over generic ribavirin availability in 2003, Three Rivers Pharmaceuticals, LLC in conjunction with Par Pharmaceutical
, was approved in 2005 to market ribavirin as Ribosphere capsules. Generic ribavirin (200 mg, no brand name) became available in 2005 from Sandoz
, Teva Pharmaceutical Industries
, and Warrick Pharmaceuticals, which is the generic arm of Schering Plough
. These products are expected to displace the brand name products paying license fees to Valeant Pharmaceuticals International
. The only present FDA-approved indication for these products is in conjunction with interferon against chronic hepatitis C with hepatic damage.
In Mexico, oral ribavirin has been available since the 1980s as an over-the-counter drug ("ribavirina," ICN pharmaceuticals Spanish tradename Vilona), for treating influenza. In this form it was occasionally brought into the U.S. for HIV/AIDS patients. However, ribavirin has proven to have little if any clinical usefulness against HIV, and it can greatly increase blood levels and also toxicity of the HIV antiviral didanosine (ddI, Videx). Other interactions with nucleoside antivirals for HIV should be considered when HIV/AIDS patients use ribavirin to treat hepatitis C (see "aidsinfo" external link).
) by chemist Joseph T. Witkowski, under the direction of laboratory director Roland K. Robins. (Robins [1926-92], a purine chemist, had earlier been the inventor of the highly successful purine-analogue pharmaceutical allopurinol
). Ribavirin was discovered as part of a systematic ICN search of antiviral and antitumor activity in synthetic nucleosides. This was inspired in part by discovery (in the 1960s) of antiviral activity from naturally-occurring purine-like nucleoside antibiotics like showdomycin, coformycin, and pyrazomycin. These agents had too much toxicity to be clinically useful (and their antiviral activity may be incidental), but they served as the starting point for pharmaceutical chemists interested in antivirals and antimetabolic chemotherapeutic agents.
In 1972 it was reported that ribavirin was active against a variety of RNA and DNA viruses in culture and in animals, without undue toxicity. Ribavirin protected mice against mortality from both A and B strains of influenza, and ICN originally planned to market it as an anti-influenza drug. Results in human trials against experimental influenza infection were mixed, however, and the FDA ultimately did not approve this indication for ribavirin use in humans, thereby causing a severe financial shock to ICN.
Although ICN was allowed in 1980 to market ribavirin, in inhalant form, for RSV infection in children, the U.S. market for this indication was small. By the time oral ribavirin was finally approved by the FDA as part of a combination treatment (with interferon) for hepatitis C in 1998, the original ICN patents on ribavirin itself had expired, and (notwithstanding subsequent patent disputes) ribavirin had become essentially a generic drug.
Classically, ribavirin is prepared from natural D-ribose by blocking the 2', 3' and 5' OH groups with benzyl groups, then derivatizing the 1' OH with an acetyl group which acts as a suitable leaving group upon nucleophilic attack. The ribose 1' carbon attack is accomplished with a 1,2,4 triazole-3-carboxymethyl ester, which directly attaches the 1' nitrogen of the triazole to the 1' carbon of the ribose, in the proper 1-β-D isomeric position. The bulky benzyl groups hinder attack at the other sugar carbons. Following purification of this intermediate, treatment with ammonia in methanolic conditions then simultaneously deblocks the ribose hydroxyls, and converts the triazole carboxymethyl ester to the carboxamide. Following this step, ribavirin may be recovered in good quantity by cooling and crystallization.
derivatives show antiviral activity with 5' hydrogen or halide, but the larger the substituent, the smaller the activity, and all proved less active than ribavirin. Note that two natural products were already known with this imidazole riboside
structure: substitution at the 5' carbon with OH results in pyrazomycin/pyrazofurin, an antibiotic with antiviral properties but unacceptable toxicity, and replacement with an amino group results in the natural purine synthetic precursor 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), which has only modest antiviral properties.
Derivatization of the triazole 5' carbon, or replacement of it with a nitrogen (i.e., the 1,2,4,5 tetrazole 3-carboxamide) also results in substantial loss of activity, as does alkyl derivatization of the 3' carboxamide nitrogen.
The 2' deoxyribose version of ribavirin (the DNA nucleoside analogue) is not active as an antiviral, suggesting strongly that ribavirin requires RNA-dependent enzymes for its antiviral activity.
Antiviral activity is retained for acetate and phosphate derivation of the ribose hydroxyls, including the triphosphate and 3', 5' cyclic phosphates, but these compounds are no more active than the parent molecule, reflecting the high efficiency of esterase
and kinase
activity in the body.
Ribavirin 5' mono- di- and tri-phosphates, in addition, are all inhibitors of certain viral RNA-dependent RNA polymerases which are a feature of anti-sense RNA viruses.
, thereby depleting intracellular pools of GTP. This mechanism may be useful in explaining the drug's general cytotoxic and anti-DNA replication effect (i.e. its toxicity) as well as some effect on DNA viral replication.
Ribavirin is an inhibitor of some viral RNA guanylyl transferase and (guanine-7N-)-methyl transferase enzymes, and this may contribute to a defective 5'-cap structure of viral mRNA transcripts and therefore inefficient viral translation for certain DNA viruses, such as vaccinia virus (a complex DNA virus). It has been suggested that incorporation of ribavirin into the 5' end of mRNA transcripts would mimic the 7-methyl guanosine endcap of cellular mRNAs, causing poor cellular translation of these. This would be a cell-toxic effect, but it does not seem to be important at therapeutic ribavirin concentrations. Any difference between cellular and viral enzyme handling of ribavirin-containing mRNA transcripts is a potential mechanism of differential inhibition of ribavirin to translation of mRNAs from viruses (including DNA viruses).
, at doses which do not clearly interfere with replication of the virus when used without interferon (see hepcassoc.org external link below).
Ribavirin is widely distributed in all tissues, including the CSF and brain. The pharmacokinetics of ribavirin is dominated by trapping of the phosphate form inside cells, particularly red blood cells (RBCs) which lack the enzyme to remove the phosphate once it has been added by kinases, and therefore attain high concentrations of the drug. Most of the kinase activity which converts the drug to active nucleotide form, is provided by adenine kinase. This enzyme is more active in virally infected cells.
The volume of distribution of ribavirin is large (2000 L/kg) and the length of time the drug is trapped varies greatly from tissue to tissue. The mean half-life for multiple doses in the body is about 12 days, but very long-term kinetics are dominated by the kinetics of RBCs (half-life 40 days). RBCs store ribavirin for the lifetime of the cells, releasing it into the body's systems when old cells are degraded in the spleen.
About a third of absorbed ribavirin is excreted into the urine unchanged, and the rest is excreted into urine as the de-ribosylated base 1,2,4-triazole 3-carboxamide, and
the hydrolysis product of this, 1,2,4-triazole 3-carboxylic acid.
are recommended during treatment of either partner and continued for six months after treatment. Women who are pregnant or planning to become pregnant are advised not to take ribavirin. Of special concern with regards to teratogenicity is ribavirin's long half-life in the body. Red blood cells (erythrocytes) concentrate the drug and are unable to excrete it, so this pool is not completely eliminated until all red cells have turned over, a process estimated to take as long as 6 months. Thus in theory, ribavirin might remain a reproductive hazard for as long as 6 months after a course of the drug has ended. Drug packaging information materials in the U.S. now reflect this warning.
Ribavirin should not be given with zidovudine
because of the increased risk of anaemia; concurrent use with didanosine
should likewise be avoided because of an increased risk of mitochondrial toxicity
.
Human respiratory syncytial virus
Human respiratory syncytial virus is a virus that causes respiratory tract infections. It is the major cause of lower respiratory tract infections and hospital visits during infancy and childhood. A prophylactic medication exists for preterm birth infants and infants with a congenital heart...
infection (individually), hepatitis C infection (used in conjunction with peginterferon alfa-2b
Peginterferon alfa-2b
Pegylated interferon alfa-2b is a treatment for hepatitis C developed by Schering-Plough, brand name is PegIntron.It was approved in January 2001....
or peginterferon alfa-2a) and other viral infections. Ribavirin is a prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
, which when metabolised resembles purine
Purine
A purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. Purines, including substituted purines and their tautomers, are the most widely distributed kind of nitrogen-containing heterocycle in nature....
RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
s. In this form it interferes with RNA metabolism required for viral replication. How it exactly affects viral replication is unknown; many mechanisms have been proposed for this (see Mechanisms of Action, below) but none of these has been proven to date. Multiple mechanisms may be responsible for its actions.
The primary observed serious adverse side effect
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, consequences of the use of a drug.Occasionally, drugs are...
of ribavirin is hemolytic anemia
Hemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...
, which may worsen preexisting cardiac disease. The mechanism for this effect is due to ribavarin's buildup inside erythrocytes. Oxidative damage to erythrocyte cell membrane is usually inhibited by glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
; however, with reduced ATP levels caused by ribavirin, glutathione levels are impaired, permitting oxidative erythrocyte cell lysis. The gradual loss of erythrocytes leads to anemia. The anemia is dose-dependent and may sometimes be compensated by decreasing dose. Ribavirin is also a teratogen
Teratology
Teratology is the study of abnormalities of physiological development. It is often thought of as the study of human birth defects, but it is much broader than that, taking in other non-birth developmental stages, including puberty; and other non-human life forms, including plants.- Etymology :The...
in some animals species and thus poses a theoretical reproductive risk in humans, remaining a hazard as long as the drug is present, which can be as long as 6 months after a course of the drug has ended.
Uses
Ribavirin is active against a number of DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
and RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es. It is a member of the nucleoside
Nucleoside
Nucleosides are glycosylamines consisting of a nucleobase bound to a ribose or deoxyribose sugar via a beta-glycosidic linkage...
antimetabolite drugs that interfere with duplication of viral genetic material. Ribavirin is active against influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
s, flavivirus
Flavivirus
Flavivirus is a genus of the family Flaviviridae. This genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, and several other viruses which may cause encephalitis....
es and agents of many viral hemorrhagic fever
Viral hemorrhagic fever
The viral hemorrhagic fevers are a diverse group of animal and human illnesses that are caused by four distinct families of RNA viruses: the families Arenaviridae, Filoviridae, Bunyaviridae, and Flaviviridae. All types of VHF are characterized by fever and bleeding disorders and all can progress...
s.
In Europe and the U.S. the oral (capsule or tablet) form of ribavirin is used in the treatment of hepatitis C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
, in combination with pegylated
Pegylated interferon alpha
Pegylated interferon alpha can refer to:* Pegylated interferon-alpha-2a* Pegylated interferon-alpha-2b...
interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
drugs.
Ribavirin is the only known treatment for a variety of viral hemorrhagic fever
Viral hemorrhagic fever
The viral hemorrhagic fevers are a diverse group of animal and human illnesses that are caused by four distinct families of RNA viruses: the families Arenaviridae, Filoviridae, Bunyaviridae, and Flaviviridae. All types of VHF are characterized by fever and bleeding disorders and all can progress...
s, including Lassa fever
Lassa fever
Lassa fever is an acute viral hemorrhagic fever caused by the Lassa virus and first described in 1969 in the town of Lassa, in Borno State, Nigeria, in the Yedseram river valley at the south end of Lake Chad. Clinical cases of the disease had been known for over a decade but had not been connected...
, Crimean-Congo hemorrhagic fever
Crimean-Congo hemorrhagic fever
Crimean–Congo hemorrhagic fever is a widespread tick-borne viral disease, a zoonosis of domestic animals and wild animals, that may affect humans. The pathogenic virus, especially common in East and West Africa, is a member of the Bunyaviridae family of RNA viruses. Clinical disease is rare in...
, and Hantavirus
Hantavirus
Hantaviruses are negative sense RNA viruses in the Bunyaviridae family. Humans may be infected with hantaviruses through rodent bites, urine, saliva or contact with rodent waste products...
infection, although data regarding these infections are scarce and the drug might be effective only in early stages.
The aerosol form has been used in the past to treat respiratory syncytial virus-related diseases in children. However, its efficacy has been called into question by multiple studies, and most institutions no longer use it. It is still used in some cases.
In Mexico, ribavirin ("ribavirina") has been sold for use against influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
. Studies have been mixed, but the derivative viramidine
Viramidine
Taribavirin is an antiviral drug in Phase III human trials, but not yet approved for pharmaceutical use. It is a prodrug of ribavirin, active against a number of DNA and RNA viruses...
may have more promise.
It has been used (in combination with ketamine
Ketamine
Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...
, midazolam
Midazolam
Midazolam is a short-acting drug in the benzodiazepine class developed by Hoffmann-La Roche in the 1970s. The drug is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It possesses profoundly potent anxiolytic,...
, and amantadine
Amantadine
Amantadine is the organic compound known formally as 1-adamantylamine or 1-aminoadamantane. The molecule consists of adamantane backbone that has an amino group substituted at one of the four methyne positions. This pharmaceutical is sold under the name Symmetrel for use both as an antiviral and an...
) in treatment of rabies
Rabies
Rabies is a viral disease that causes acute encephalitis in warm-blooded animals. It is zoonotic , most commonly by a bite from an infected animal. For a human, rabies is almost invariably fatal if post-exposure prophylaxis is not administered prior to the onset of severe symptoms...
.
This drug is also used to control the life span of enterovirus 71 which causes hand, foot, and mouth disease.
Experimental uses
Experimental data indicate that ribavirin may have useful activity against many viruses of interest, including avian influenzaInfluenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
, hepatitis B, polio, measles
Measles
Measles, also known as rubeola or morbilli, is an infection of the respiratory system caused by a virus, specifically a paramyxovirus of the genus Morbillivirus. Morbilliviruses, like other paramyxoviruses, are enveloped, single-stranded, negative-sense RNA viruses...
, Canine distemper
Canine distemper
Canine distemper is a viral disease that affects animals in the families Canidae, Mustelidae, Mephitidae, Hyaenidae, Ailuridae, Procyonidae, Pinnipedia, some Viverridae and Felidae...
and smallpox
Smallpox
Smallpox was an infectious disease unique to humans, caused by either of two virus variants, Variola major and Variola minor. The disease is also known by the Latin names Variola or Variola vera, which is a derivative of the Latin varius, meaning "spotted", or varus, meaning "pimple"...
. Ribavirin is active in a hamster model of yellow fever
Yellow fever
Yellow fever is an acute viral hemorrhagic disease. The virus is a 40 to 50 nm enveloped RNA virus with positive sense of the Flaviviridae family....
, a finding which is not surprising, given the familial relationship of yellow fever
Yellow fever
Yellow fever is an acute viral hemorrhagic disease. The virus is a 40 to 50 nm enveloped RNA virus with positive sense of the Flaviviridae family....
and hepatitis C
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
viruses as flaviviridae
Flaviviridae
The Flaviviridae are a family of viruses that are primarily spread through arthropod vectors . The family gets its name from Yellow Fever virus, a type virus of Flaviviridae; flavus means yellow in Latin...
. Ribavirin is active against other important flaviviridae
Flaviviridae
The Flaviviridae are a family of viruses that are primarily spread through arthropod vectors . The family gets its name from Yellow Fever virus, a type virus of Flaviviridae; flavus means yellow in Latin...
such as West Nile virus
West Nile virus
West Nile virus is a virus of the family Flaviviridae. Part of the Japanese encephalitis antigenic complex of viruses, it is found in both tropical and temperate regions. It mainly infects birds, but is known to infect humans, horses, dogs, cats, bats, chipmunks, skunks, squirrels, domestic...
and dengue fever
Dengue fever
Dengue fever , also known as breakbone fever, is an infectious tropical disease caused by the dengue virus. Symptoms include fever, headache, muscle and joint pains, and a characteristic skin rash that is similar to measles...
.
Ribavirin has also been used as a treatment for herpes simplex virus. One small study found that ribavirin treatment reduced the severity of herpes outbreaks and promoted recovery, as compared with placebo treatment. Another study found that ribavirin potentiated the antiviral effect of acyclovir.
Ribavirin's present generic status is expected to slow research into new uses, however.
Marketing
Oral ribavirin, as Rebetol, was marketed in the U.S. until 2005 by Schering PloughSchering-Plough
Schering-Plough Corporation was a United States-based pharmaceutical company. It was founded in 1851 by Ernst Christian Friedrich Schering as Schering AG in Germany. In 1971, the Schering Corporation merged with Plough to form Schering-Plough. On November 4, 2009 Merck & Co...
with royalty payments for licensing made to Valeant Pharmaceuticals International
Valeant Pharmaceuticals International
Valeant Pharmaceuticals International, Inc. is a pharmaceutical company with activities spanning the drug discovery pipeline from target identification through clinical trials and commercialization. The focus of the company is on neurology, dermatology and infectious disease with several drugs in...
(see History below). It was also marketed as Copegus tablets by Roche Pharmaceuticals under a separate license to Valeant Pharmaceuticals International
Valeant Pharmaceuticals International
Valeant Pharmaceuticals International, Inc. is a pharmaceutical company with activities spanning the drug discovery pipeline from target identification through clinical trials and commercialization. The focus of the company is on neurology, dermatology and infectious disease with several drugs in...
. After concluding patent disputes over generic ribavirin availability in 2003, Three Rivers Pharmaceuticals, LLC in conjunction with Par Pharmaceutical
Par Pharmaceutical
Par Pharmaceutical develops, manufactures and markets generic and branded specialty pharmaceuticals. Par was founded in 1978 and initially traded on the New York Stock Exchange in 1987...
, was approved in 2005 to market ribavirin as Ribosphere capsules. Generic ribavirin (200 mg, no brand name) became available in 2005 from Sandoz
Sandoz
Founded in 2003, Sandoz presently is the generic drug subsidiary of Novartis, a multinational pharmaceutical company. The company develops, manufactures and markets generic drugs as well as pharmaceutical and biotechnological active ingredients....
, Teva Pharmaceutical Industries
Teva Pharmaceutical Industries
Teva Pharmaceutical Industries Ltd. , is an international pharmaceutical company headquartered in Petah Tikva, Israel. It specializes in generic and proprietary pharmaceuticals and active pharmaceutical ingredients...
, and Warrick Pharmaceuticals, which is the generic arm of Schering Plough
Schering-Plough
Schering-Plough Corporation was a United States-based pharmaceutical company. It was founded in 1851 by Ernst Christian Friedrich Schering as Schering AG in Germany. In 1971, the Schering Corporation merged with Plough to form Schering-Plough. On November 4, 2009 Merck & Co...
. These products are expected to displace the brand name products paying license fees to Valeant Pharmaceuticals International
Valeant Pharmaceuticals International
Valeant Pharmaceuticals International, Inc. is a pharmaceutical company with activities spanning the drug discovery pipeline from target identification through clinical trials and commercialization. The focus of the company is on neurology, dermatology and infectious disease with several drugs in...
. The only present FDA-approved indication for these products is in conjunction with interferon against chronic hepatitis C with hepatic damage.
In Mexico, oral ribavirin has been available since the 1980s as an over-the-counter drug ("ribavirina," ICN pharmaceuticals Spanish tradename Vilona), for treating influenza. In this form it was occasionally brought into the U.S. for HIV/AIDS patients. However, ribavirin has proven to have little if any clinical usefulness against HIV, and it can greatly increase blood levels and also toxicity of the HIV antiviral didanosine (ddI, Videx). Other interactions with nucleoside antivirals for HIV should be considered when HIV/AIDS patients use ribavirin to treat hepatitis C (see "aidsinfo" external link).
History
Ribavirin (originally also known as Virazole) is a synthetic chemical not found in nature. It was first synthesized in 1970 (Lau, 2002—see hepcassoc.org external link below) at ICN Pharmaceuticals, Inc. (later Valeant Pharmaceuticals InternationalValeant Pharmaceuticals International
Valeant Pharmaceuticals International, Inc. is a pharmaceutical company with activities spanning the drug discovery pipeline from target identification through clinical trials and commercialization. The focus of the company is on neurology, dermatology and infectious disease with several drugs in...
) by chemist Joseph T. Witkowski, under the direction of laboratory director Roland K. Robins. (Robins [1926-92], a purine chemist, had earlier been the inventor of the highly successful purine-analogue pharmaceutical allopurinol
Allopurinol
Allopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout.- Mechanism of action :...
). Ribavirin was discovered as part of a systematic ICN search of antiviral and antitumor activity in synthetic nucleosides. This was inspired in part by discovery (in the 1960s) of antiviral activity from naturally-occurring purine-like nucleoside antibiotics like showdomycin, coformycin, and pyrazomycin. These agents had too much toxicity to be clinically useful (and their antiviral activity may be incidental), but they served as the starting point for pharmaceutical chemists interested in antivirals and antimetabolic chemotherapeutic agents.
In 1972 it was reported that ribavirin was active against a variety of RNA and DNA viruses in culture and in animals, without undue toxicity. Ribavirin protected mice against mortality from both A and B strains of influenza, and ICN originally planned to market it as an anti-influenza drug. Results in human trials against experimental influenza infection were mixed, however, and the FDA ultimately did not approve this indication for ribavirin use in humans, thereby causing a severe financial shock to ICN.
Although ICN was allowed in 1980 to market ribavirin, in inhalant form, for RSV infection in children, the U.S. market for this indication was small. By the time oral ribavirin was finally approved by the FDA as part of a combination treatment (with interferon) for hepatitis C in 1998, the original ICN patents on ribavirin itself had expired, and (notwithstanding subsequent patent disputes) ribavirin had become essentially a generic drug.
Chemistry
Physically ribavirin is similar to the sugar D-ribose from which it is derived. It is freely soluble in water, and is re-crystallized as fine silvery needles from boiling methanol. The three free sugar hydroxyls make the pure drug hydrophilic enough that it is only sparingly soluble in anhydrous ethanol.Classically, ribavirin is prepared from natural D-ribose by blocking the 2', 3' and 5' OH groups with benzyl groups, then derivatizing the 1' OH with an acetyl group which acts as a suitable leaving group upon nucleophilic attack. The ribose 1' carbon attack is accomplished with a 1,2,4 triazole-3-carboxymethyl ester, which directly attaches the 1' nitrogen of the triazole to the 1' carbon of the ribose, in the proper 1-β-D isomeric position. The bulky benzyl groups hinder attack at the other sugar carbons. Following purification of this intermediate, treatment with ammonia in methanolic conditions then simultaneously deblocks the ribose hydroxyls, and converts the triazole carboxymethyl ester to the carboxamide. Following this step, ribavirin may be recovered in good quantity by cooling and crystallization.
Derivatives
Ribavirin is possibly best viewed as a ribosyl purine analogue with an incomplete purine 6-membered ring. This structural resemblance historically prompted replacement of the 2' nitrogen of the triazole with a carbon (which becomes the 5' carbon in an imidazole), in an attempt to partly "fill out" the second ring--- but to no great effect. Such 5' imidazole ribosideRiboside
A riboside is any glycoside of ribose. Ribosides in the form of ribonucleosides and ribonucleotides play an important role in biochemistry....
derivatives show antiviral activity with 5' hydrogen or halide, but the larger the substituent, the smaller the activity, and all proved less active than ribavirin. Note that two natural products were already known with this imidazole riboside
Riboside
A riboside is any glycoside of ribose. Ribosides in the form of ribonucleosides and ribonucleotides play an important role in biochemistry....
structure: substitution at the 5' carbon with OH results in pyrazomycin/pyrazofurin, an antibiotic with antiviral properties but unacceptable toxicity, and replacement with an amino group results in the natural purine synthetic precursor 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), which has only modest antiviral properties.
Derivatization of the triazole 5' carbon, or replacement of it with a nitrogen (i.e., the 1,2,4,5 tetrazole 3-carboxamide) also results in substantial loss of activity, as does alkyl derivatization of the 3' carboxamide nitrogen.
The 2' deoxyribose version of ribavirin (the DNA nucleoside analogue) is not active as an antiviral, suggesting strongly that ribavirin requires RNA-dependent enzymes for its antiviral activity.
Antiviral activity is retained for acetate and phosphate derivation of the ribose hydroxyls, including the triphosphate and 3', 5' cyclic phosphates, but these compounds are no more active than the parent molecule, reflecting the high efficiency of esterase
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, and their biological function.- EC classification/list...
and kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
activity in the body.
Taribavirin (viramidine)
The most successful ribavirin derivative to date is the 3-carboxamidine derivative of the parent 3-carboxamide, first reported in 1973 by J.T.Witkowski et al., and now called taribavirin (former names viramidine and ribamidine). This drug shows a similar spectrum of antiviral activity to ribavirin, which is not surprising as it is now known to be a pro-drug for ribavirin. Viramidine, however, has useful properties of less erythrocyte-trapping and better liver-targeting than ribavirin. The first property is due to viramidine's basic amidine group which inhibits drug entry into RBCs, and the second property is probably due to increased concentration of the enzymes which convert amidine to amide, in liver tissue. Viramidine is in phase III human trials and may one day be used in place of ribavirin, at least against certain kinds of viral hepatitis. Viramidine's slightly superior toxicological properties may eventually cause it to replace ribavirin in all uses of ribavirin.RNA viruses
Ribavirin's carboxamide group can make the native nucleoside drug resemble adenosine or guanosine, depending on its rotation. For this reason, when ribavirin is incorporated into RNA, as a base analog of either adenine or guanine, it pairs equally well with either uracil or cytosine, inducing mutations in RNA-dependent replication in RNA viruses. Such hypermutation can be lethal to RNA viruses.Ribavirin 5' mono- di- and tri-phosphates, in addition, are all inhibitors of certain viral RNA-dependent RNA polymerases which are a feature of anti-sense RNA viruses.
DNA viruses
Neither of these mechanisms explains ribavirin's effect on many DNA viruses, which is more of a mystery, especially given the complete inactivity of ribavirin's 2' deoxyribose analogue noted above, which suggests that the drug functions only as an RNA nucleoside mimic, and never a DNA nucleoside mimic. Ribavirin 5'-monophosphate inhibits cellular inosine monophosphate dehydrogenaseIMP dehydrogenase
IMP dehydrogenase is an enzyme that converts inosine monophosphate to xanthosine monophosphate:The structure of this enzyme is composed of a TIM barrel domain with two CBS domains inserted within a loop.It is inhibited by Mycophenolic acid.- Examples :...
, thereby depleting intracellular pools of GTP. This mechanism may be useful in explaining the drug's general cytotoxic and anti-DNA replication effect (i.e. its toxicity) as well as some effect on DNA viral replication.
Ribavirin is an inhibitor of some viral RNA guanylyl transferase and (guanine-7N-)-methyl transferase enzymes, and this may contribute to a defective 5'-cap structure of viral mRNA transcripts and therefore inefficient viral translation for certain DNA viruses, such as vaccinia virus (a complex DNA virus). It has been suggested that incorporation of ribavirin into the 5' end of mRNA transcripts would mimic the 7-methyl guanosine endcap of cellular mRNAs, causing poor cellular translation of these. This would be a cell-toxic effect, but it does not seem to be important at therapeutic ribavirin concentrations. Any difference between cellular and viral enzyme handling of ribavirin-containing mRNA transcripts is a potential mechanism of differential inhibition of ribavirin to translation of mRNAs from viruses (including DNA viruses).
Special mechanisms
Finally, ribavirin is known to enhance host T-cell-mediated immunity against viral infection through helping to switch the host T-cell phenotype from type 2 to type 1. This may explain ribavirin's antiviral activity against some viruses such as hepatitis CHepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...
, at doses which do not clearly interfere with replication of the virus when used without interferon (see hepcassoc.org external link below).
Pharmacokinetics
Ribavirin is absorbed from the GI tract probably by nucleoside transporters. Absorption is about 45%, and this is modestly increased (to about 75%) by a fatty meal. Once in the plasma, ribavirin is transported through the cell membrane also by nucleoside transporters.Ribavirin is widely distributed in all tissues, including the CSF and brain. The pharmacokinetics of ribavirin is dominated by trapping of the phosphate form inside cells, particularly red blood cells (RBCs) which lack the enzyme to remove the phosphate once it has been added by kinases, and therefore attain high concentrations of the drug. Most of the kinase activity which converts the drug to active nucleotide form, is provided by adenine kinase. This enzyme is more active in virally infected cells.
The volume of distribution of ribavirin is large (2000 L/kg) and the length of time the drug is trapped varies greatly from tissue to tissue. The mean half-life for multiple doses in the body is about 12 days, but very long-term kinetics are dominated by the kinetics of RBCs (half-life 40 days). RBCs store ribavirin for the lifetime of the cells, releasing it into the body's systems when old cells are degraded in the spleen.
About a third of absorbed ribavirin is excreted into the urine unchanged, and the rest is excreted into urine as the de-ribosylated base 1,2,4-triazole 3-carboxamide, and
the hydrolysis product of this, 1,2,4-triazole 3-carboxylic acid.
Adverse effects
Ribavirin is not substantially incorporated into DNA, but does have a dose-dependent inhibiting effect on DNA synthesis, as well as having other effects on gene-expression. Possibly for these reasons, significant teratogenic effects have been noted in all non-primate animal species on which ribavirin has been tested. Ribavirin did not produce birth defects in baboons, but this should not be an indication that it is safe in humans. Therefore, two simultaneous forms of birth controlBirth control
Birth control is an umbrella term for several techniques and methods used to prevent fertilization or to interrupt pregnancy at various stages. Birth control techniques and methods include contraception , contragestion and abortion...
are recommended during treatment of either partner and continued for six months after treatment. Women who are pregnant or planning to become pregnant are advised not to take ribavirin. Of special concern with regards to teratogenicity is ribavirin's long half-life in the body. Red blood cells (erythrocytes) concentrate the drug and are unable to excrete it, so this pool is not completely eliminated until all red cells have turned over, a process estimated to take as long as 6 months. Thus in theory, ribavirin might remain a reproductive hazard for as long as 6 months after a course of the drug has ended. Drug packaging information materials in the U.S. now reflect this warning.
Ribavirin should not be given with zidovudine
Zidovudine
Zidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....
because of the increased risk of anaemia; concurrent use with didanosine
Didanosine
Didanosine is sold under the trade names Videx and Videx EC. It is a reverse transcriptase inhibitor, effective against HIV and used in combination with other antiretroviral drug therapy as part of highly active antiretroviral therapy .-History:The related pro-drug of didanosine,...
should likewise be avoided because of an increased risk of mitochondrial toxicity
Mitochondrial toxicity
Mitochondrial toxicity is a condition in which the mitochondria of a body's cells become damaged or decline significantly in number; it occurs as a side effect of certain antiretroviral drugs used to treat human immunodeficiency virus, or HIV.-Causes:...
.
External links
- http://www.hepcassoc.org/news/article39.html
- http://www.jac.oxfordjournals.org/cgi/content/full/52/4/543
- http://aidsinfo.nih.gov/drugs/htmldrug_tech.asp?int_id=0028
- http://www.jac.oxfordjournals.org/cgi/reprint/dki405v1
- Information on Ribavirin