Rimantadine

Rimantadine (INN, sold under the trade name Flumadine) is an orally administered antiviral drug[1] used to treat, and in rare cases prevent, influenzavirus A infection. When taken within one to two days of developing symptoms, rimantadine can shorten the duration and moderate the severity of influenza. Both rimantadine and the similar drug amantadine are derivates of adamantane. Rimantadine was approved by the Food and Drug Administration (FDA) in 1994.

Rimantadine was approved for medical use in 1993.[2] 100% of seasonal H3N2 and 2009 pandemic flu samples tested have shown resistance to rimantadine and it is no longer recommended to prescribe for treatment of the flu.[3]

Rimantadine
Rimantadine
Rimantadine ball-and-stick model
Clinical data
Trade namesFlumadine
AHFS/Drugs.comMonograph
MedlinePlusa698029
Pregnancy
category
  • C (United States)
Routes of
administration
Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailabilitywell absorbed
Protein binding40%
MetabolismHepatic hydroxylation and glucuronidation
Elimination half-life25.4 ± 6.3 hours
ExcretionRenal
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
Chemical and physical data
FormulaC12H21N
Molar mass179.302 g/mol
3D model (JSmol)
ChiralityRacemic mixture
  (verify)

Medical use

Rimantadine is believed to inhibit influenza's viral replication, possibly by preventing the uncoating of the virus's protective shells, which are the envelope and capsid. Genetic studies suggest that the virus M2 protein, an ion channel specified by virion M2 gene, plays an important role in the susceptibility of influenza A virus to inhibition by rimantadine. Resistance to rimantadine can occur as a result of amino acid substitutions at certain locations in the transmembrane region of M2. This prevents binding of the antiviral to the channel.[4]

Rimantadine, like its antiviral cousin amantadine, possesses some NMDA antagonistic properties and is used as an antiparkinsonic drug (i.e., in the treatment of Parkinson's disease). However, in general, neither rimantadine nor amantadine is a preferred agent for this therapy and would be reserved for cases of the disease that are less responsive to front-line treatments.

Drug interactions

Taking paracetamol (acetaminophen, Tylenol) or acetylsalicylic acid (aspirin) while taking rimantadine is known to reduce the body's uptake of rimantadine by approximately 12%.[5] Cimetidine also affects the body's uptake of rimantadine.

Side effects

Rimantadine can produce gastrointestinal and central nervous system adverse effects. Approximately 6% of patients (compared to 4% of patients taking a placebo) reported side-effects at a dosage of 200 mg/d.[6] Common side effects include:

  • nausea
  • upset stomach
  • nervousness
  • tiredness
  • lightheadedness
  • trouble sleeping
  • difficulty concentrating

History

Rimantadine was discovered in 1963[7][8] and patented in 1965 in the US by William W. Prichard in Du Pont & Co., Wilmington, Delaware (patent on new chemical compound U.S. Patent 3,352,912, 1965 and on the first method of synthesis U.S. Patent 3,592,934, 1967).[9][10] Prichard's methods of synthesis of rimantadine from the corresponding ketone oxime were based on its reduction with lithium aluminum hydride.

See also

References

  1. ^ Govorkova EA, Fang HB, Tan M, Webster RG (December 2004). "Neuraminidase Inhibitor-Rimantadine Combinations Exert Additive and Synergistic Anti-Influenza Virus Effects in MDCK Cells". Antimicrobial Agents and Chemotherapy. 48 (12): 4855–63. doi:10.1128/AAC.48.12.4855-4863.2004. PMC 529183. PMID 15561867.
  2. ^ Long, Sarah S.; Pickering, Larry K.; Prober, Charles G. (2012). Principles and Practice of Pediatric Infectious Disease. Elsevier Health Sciences. p. 1502. ISBN 1437727026.
  3. ^ Antiviral Agents for the Treatment and Chemoprophylaxis of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP)
  4. ^ Jing X, Ma C, Ohigashi Y, et al. (August 2008). "Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel". Proc. Natl. Acad. Sci. U.S.A. 105 (31): 10967–72. doi:10.1073/pnas.0804958105. PMC 2492755. PMID 18669647.
  5. ^ "fda.gov". Archived from the original on June 30, 2005. Retrieved 2008-11-05.
  6. ^ "CDC - Influenza (Flu) | Antivirals: Side-Effects | REMOVED!". Retrieved 2008-11-05.
  7. ^ US patent 3352912 to W. W. Prichard
  8. ^ United States Patent № 4551552: Process for preparing rimantadine: Rimantadine and related compounds useful as antivirals were first described by Prichard in U.S. Pat. Nos. 3,352,912 and 3,592,934. Both patents describe the preparation of rimantadine from the corresponding ketone oxime by reduction with lithium aluminum hydride.
  9. ^ United States Patent № 4551552: Process for preparing rimantadine
  10. ^ Zlydnikov, D. M.; Kubar, O. I.; Kovaleva, T. P.; Kamforin, L. E. "Study of Rimantadine in the USSR: A Review of the Literature". Clinical Infectious Diseases. 3: 408–421. doi:10.1093/clinids/3.3.408.

External links

6-Br-APB

6-Br-APB is a synthetic compound that acts as a selective D1 agonist, with the (R)-enantiomer being a potent full agonist, while the (S) enantiomer retains its D1 selectivity but is a weak partial agonist. (R)-6-Br-APB and similar D1-selective full agonists like SKF-81,297 and SKF-82,958 produce characteristic anorectic effects, stereotyped behaviour and self-administration in animals, with a similar but not identical profile to that of dopaminergic stimulants such as amphetamine.

Adapromine

Adapromine is an antiviral drug of the adamantane group related to amantadine (1-aminoadamantane), rimantadine (1-(1-aminoethyl)adamantane), and memantine (1-amino-3,5-dimethyladamantane) that is marketed in Russia for the treatment and prevention of influenza. It is an alkyl analogue of rimantadine and is similar to rimantadine in its antiviral activity but possesses a broader spectrum of action, being effective against influenza viruses of both type A and B. Strains of type A influenza virus with resistance to adapromine and rimantadine and the related drug deitiforine were encountered in Mongolia and the Soviet Union in the 1980s.Electroencephalography (EEG) studies of animals suggest that adapromine and related adamantanes including amantadine, bromantane (1-amino-2-bromophenyladamantane), and memantine have psychostimulant-like and possibly antidepressant-like effects, and that these effects may be mediated via catecholaminergic processes. These psychostimulant effects differ qualitatively from those of conventional psychostimulants like amphetamine however, and the adamantane derivatives have been described contrarily as "adaptogens" and as "actoprotectors".In 2004, it was discovered that amantadine and memantine bind to and act as agonists of the σ1 receptor (Ki = 7.44 µM and 2.60 µM, respectively) and that activation of the σ1 receptor is involved in the dopaminergic effects of amantadine at therapeutically relevant concentrations. These findings might also extend to the other adamantanes such as adapromine, rimantadine, and bromantane and could explain the psychostimulant-like effects of this family of compounds.

Amantadine

Amantadine (trade name Symmetrel, by Endo Pharmaceuticals) is a medication that has U.S. Food and Drug Administration approval for use both as an antiviral and an antiparkinsonian medication. It is the organic compound 1-adamantylamine or 1-aminoadamantane, meaning it consists of an adamantane backbone that has an amino group substituted at one of the four methyne positions. Rimantadine is a closely related derivative of adamantane with similar biological properties.

Apart from medical uses, this compound is useful as a building block in organic synthesis, allowing the insertion of an adamantyl group.

According to the U.S. Centers for Disease Control and Prevention (CDC) 100% of seasonal H3N2 and 2009 pandemic flu samples tested showed resistance to adamantanes, and amantadine is no longer recommended for treatment of influenza in the United States. Additionally, its effectiveness as an antiparkinsonian drug is undetermined, with a 2003 Cochrane Review concluding that there was insufficient evidence in support of or against its efficacy and safety.

Bromantane

Bromantane, sold under the brand name Ladasten, is an atypical psychostimulant and anxiolytic drug of the adamantane family related to amantadine and memantine which is used in Russia in the treatment of neurasthenia. Although the effects of the bromantane have been determined to be dependent on the dopaminergic and possibly serotonergic neurotransmitter systems, its exact mechanism of action is unknown, and it is distinct in its properties relative to typical psychostimulants such as amphetamine. Because of its unique aspects, bromantane has sometimes been described instead as an adaptogen and actoprotector.

CRL-40,940

CRL-40,940 (also known as flmodafinil, bisfluoromodafinil and lauflumide) is the bisfluoro analog of modafinil. It is a eugeroic as well as a weak dopamine reuptake inhibitor. Its inventors claim that it is more effective than modafinil and adrafinil, with fewer side effects. It was patented in 2013, and Phase I clinical trials have been underway since December 2015.

Cilobamine

Cilobamine is a drug which acts as a norepinephrine-dopamine reuptake inhibitor (NDRI) and has stimulant and antidepressant effects.It can clearly be seen that the structure is based on dichloroisoprenaline that has been fused onto the bicycloalkane scaffold.

Gamfexine

Gamfexine (WIN-1,344) is a centrally acting stimulant drug, which was tested as an adjunct treatment for withdrawn patients with schizophrenia, but while effective for treating withdrawal it made psychotic symptoms worse.

Influenza A virus subtype H3N1

H3N1 is a subtype of the species Influenza A virus, mostly affecting pigs.

The known subtypes of Influenza A virus that create influenza in pigs and are endemic in pigs are H1N1, H1N2, H3N1 and H3N2.

Influenza treatment

Treatments for influenza include a range of medications and therapies that are used in response to disease influenza. Treatments may either directly target the influenza virus itself; or instead they may just offer relief to symptoms of the disease, while the body's own immune system works to recover from infection.The two main classes of antiviral drugs used against influenza are neuraminidase inhibitors, such as zanamivir and oseltamivir, or inhibitors of the viral M2 protein, such as amantadine and rimantadine. These drugs can reduce the severity of symptoms if taken soon after infection and can also be taken to decrease the risk of infection. However, virus strains have emerged that show drug resistance to both classes of drug.

Jānis Polis

Jānis Polis (25 June 1938 – 12 April 2011) was a Soviet and Latvian pharmacologist and the developer of one of the first methods of synthesis of rimantadine, which was discovered in 1963 by William W. Prichard of Du Pont & Co. He was born in Eleja parish, Latvia. On 6 February 2009, Polis was awarded the WIPO Award for Outstanding Inventors. Polis died in Riga, Latvia on 12 April 2011 at the age of 72.

M2 proton channel

The Matrix-2 (M2) protein is a proton-selective ion channel protein, integral in the viral envelope of the influenza A virus. The channel itself is a homotetramer (consists of four identical M2 units), where the units are helices stabilized by two disulfide bonds, and is activated by low pH. The M2 protein is encoded on the seventh RNA segment together with the M1 protein. Proton conductance by the M2 protein in influenza A is essential for viral replication.

Methylenedioxycathinone

3,4-Methylenedioxycathinone (also known as MDC, Nitrilone, Amylone and βk-MDA) is an empathogen and stimulant of the phenethylamine, amphetamine, and cathinone classes and the β-keto analogue of MDA.Methylenedioxycathinone has been investigated as antidepressant and antiparkinson agent.

Optaflu

Optaflu is a cell culture derived influenza vaccine manufactured by Novartis.

Picilorex

Picilorex (INN; brand name Roxenan) is an anorectic which is no longer marketed. It is a monoamine reuptake inhibitor.

Psychotropic alkylamines

Psychotropic alkylamines are alkylamines that share the critical property of not containing an aromatic nucleus, but are still biologically active. While many of these molecules are stimulants (some of them natural), others are antiviral, have competitive NMDA antagonist activity, or are nicotinic receptor antagonists.

SKF-77,434

SKF-77,434 is a drug which acts as a selective dopamine D1 receptor partial agonist, and has stimulant and anorectic effects. Unlike other D1 agonists with higher efficacy such as SKF-81,297 and 6-Br-APB, SKF-77,434 does not maintain self-administration in animal studies, and so has been researched as a potential treatment for cocaine addiction.

SKF-81,297

SKF-81,297 is a synthetic drug of the benzazepine chemical class that acts as a selective dopamine D1/D5 receptor full agonist, and produces a characteristic stimulant-like pattern of anorexia, hyperactivity and self-administration in animals. This profile is shared with several related drugs such as 6-Br-APB and SKF-82,958, but not with certain other D1 full agonists such as A-77,636, reflecting functional selectivity of D1 activation. Newer findings reveal that SKF-81,297 additionally acts as a partial agonist at D1-D2 receptor heteromers.

Tromantadine

Tromantadine is an antiviral medicine used to treat herpes simplex virus. It is available in a topical gel under trade names Viru-Merz and Viru-Merz Serol. Its performance is similar to aciclovir.Like rimantadine, amantadine, and adapromine, tromantadine is a derivative of adamantane.

William DeGrado

William F. "Bill" DeGrado, Ph.D., is the Professor of Pharmaceutical Chemistry at the University of California, San Francisco (UCSF) and a member of the National Academy of Sciences.

He received a B.S. (chemistry) from Kalamazoo College and a Ph.D. (Chemistry) from the University of Chicago in 1977 working with Emil T. Kaiser and F. Kezdy. His graduate work focused on the design of the oxime resin for solid-phase synthesis, which was used for synthesis of protected peptides and is still in use for various types of combinatorial chemistry today. He also used peptide design to demonstrate that melittin adopts an amphiphilic helical structure, which is responsible for its membrane-disrupting activity.

He first held an industrial position at DuPont Central Research & Development (later DuPont Merck Pharmaceutical Company). He transitioned to academia in 1996, joining the University of Pennsylvania as the George W. Raiziss professor of biochemistry and biophysics and then moved to UCSF in 2011.

His published research includes contributions to the fields of protein design, synthesis of peptidomimetics, and characterization of membrane-active peptides and proteins, most notably the M2 protein.

The M2 proton channel from Influenza A virus. DeGrado’s early work with the groups of Robert Lamb and Larry Pinto established the overall structure and mechanism of the M2 proton channel, which is the target of the anti-influenza drugs, amantadine and rimantadine. A decade later their crystallographic, and NMR structures defined the fine details of the binding site for these drugs and explained the mechanism of the growing problem of amantadine-resistance. With Michael Klein, Robert Lamb and Larry Pinto, DeGrado extensively characterized the physiological properties of many drug-resistant mutants of the channel, identified those most likely to lead to resistance, and designed new drugs to address the problem of drug-resistant forms of influenza A virus.

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