Rimantadine

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Rimantadine (INN, sold under the trade name Flumadine<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>) is an orally administered antiviral drug<ref name="pmid15561867">Template:Cite journal</ref> 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. Rimantadine can mitigate symptoms, including fever.<ref>Template:Cite journal</ref> Both rimantadine and the similar drug amantadine are derivates of adamantane. Rimantadine is found to be more effective than amantadine because when used the patient displays fewer symptoms.<ref>Template:Cite journal</ref> Rimantadine was approved by the Food and Drug Administration (FDA) in 1994.

Rimantadine was approved for medical use in 1993.<ref>Template:Cite book</ref> 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.<ref>Antiviral Agents for the Treatment and Chemoprophylaxis of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP)</ref>

Medical uses

Influenza A

Rimantadine inhibits influenza activity by binding to amino acids in the M2 transmembrane channel and blocking proton transport across the M2 channel.<ref>Template:Cite journal</ref> 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. The M2 channel is known to be responsible for viral replication in the influenza virus. 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.Template:Citation needed

Rimantadine is bound inside the pore to amantadine specific amino acid binding sites with hydrogen binding and van der Waals interactions.<ref>Template:Cite journal</ref> The ammonium group (with neighboring water molecules) is positioned towards the C terminus with the amantadane group is positioned towards the N-terminus when bound inside the M2 pore.Template:Citation needed

File:Rimantadine S31N Mutation Binding.png

Rimantadine S31N Mutation Binding

Influenza resistance

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.<ref name="pmid18669647">Template:Cite journal</ref>

The mutation S31N binding site with rimantadine is shown in the image to the left. It shows rimantadine binding into lumenal (top) or peripheral (bottom) binding sites with influenza M2 channel Serine 31 (gold) or Asparagine 31 (blue).Template:Citation needed

Rimantadine enantiomers interactions with M2

Rimantadine, when sold as flumadine, is present as a racemic mixture; the R and S states are both present in the drug. Solid state NMR studies have shown that the R enantiomer has a stronger binding affinity to the M2 channel pore than the S-enantiomer of rimantadine.<ref>Template:Cite journal</ref> Antiviral assay and electrophysiology studies show that there is no significant difference between the R and S enantiomers in binding affinity to amino acids in the M2 channel.<ref>Template:Cite journal</ref> Since the enantiomers have similar binding affinity, they also have similar ability to block the channel pore and work as an effective antiviral.Template:Citation needed

Rimantadine enantiomers R and S are pictured interacting with the M2 pore below to the right. This image shows that there is not a significant modeled difference between the R and S enantiomers.Template:Citation needed

Parkinson's disease

Rimantadine, like its antiviral cousin amantadine, possesses antiparkinsonian activity and can be used in the treatment of Parkinson's disease.<ref name="EvidenteAdlerCaviness1999">Template:Cite journal</ref><ref name="SingerPapapetropoulos2005">Template:Cite journal</ref> 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.Template:Citation needed

Others

Rimantadine is shown to be effective against other RNA-containing viruses. It can treat arboviruses like Saint Louis encephalitis and Sindbis. Other viruses that can be treated with Rimantadine include respiratory synctialTemplate:Typo help inline and parainfluenza viruses.<ref>Template:Cite journal</ref> Rimantadine has also been shown to treat chronic hepatitis C.<ref>Template:Cite journal</ref>

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Common side effects include:Template:Citation needed

• Nausea
• Upset stomach
• Nervousness
• Tiredness
• Lightheadedness
• Trouble sleeping (insomnia)
• Difficulty concentrating
• Confusion

Rimantadine shows fewer CNS symptoms than its sister drug amantadine.<ref>Template:Cite journal</ref>

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%.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• Cimetidine also affects the body's uptake of rimantadine.Template:Citation needed
• Taking anticholinergic drugs with amantadine may increase underlying seizure disorders and aggravate congestive heart failure.<ref>Template:Cite journal</ref>

Pharmacology

Pharmacodynamics

The related drugs memantine and to a much lesser extent amantadine are known to act as NMDA receptor antagonists.<ref name="DanyszParsonsKornhuber1997">Template:Cite journal</ref><ref name="DanyszDekundyScheschonka2021">Template:Cite journal</ref> The affinity of rimantadine for the NMDA receptor does not seem to have been reported.<ref name="BindingDB">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="PDSPKiDatabase">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="PubMed-Search">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Analogues of rimantadine are known to act as NMDA receptor antagonists.<ref name="CampsDuqueVázquez2008">Template:Cite journal</ref>

Chemistry

Synthesis

File:Rimantadine synthesis 1.PNG

Rimantadine synthesis

1-carboxyadamatanones are reduced with sodium borohydride to create racemic hydroxy acid. Excess methyllithium is then added to create methyl ketones which when reduced with lithium aluminum hydride gives the amine group.<ref>Template:Cite journal</ref>

The synthesis pictured to the left is a synthesis of rimantadine as synthesized in Europe.Template:Citation needed

History

Rimantadine was discovered in 1963<ref>US patent 3352912 to W. W. Prichard</ref><ref>United States Patent No. 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.</ref> and patented in 1965 in the US by William W. Prichard in Du Pont & Co., Wilmington, Delaware (patent on new chemical compound {{#if:3352912 |[{{#ifeq:|uspto|http://patft.uspto.gov/netacgi/nph-Parser?patentnumber=%7Chttps://patents.google.com/patent/US}}{{#iferror:{{#expr:3352912 }}|3352912}} U.S. patent {{#ifeq:Template:Replace|Template:Digits|Template:Replace|3352912}}] |{{US patent|123456|link text}}}}, 1965 and on the first method of synthesis {{#if:3592934 |[{{#ifeq:|uspto|http://patft.uspto.gov/netacgi/nph-Parser?patentnumber=%7Chttps://patents.google.com/patent/US}}{{#iferror:{{#expr:3592934 }}|3592934}} U.S. patent {{#ifeq:Template:Replace|Template:Digits|Template:Replace|3592934}}] |{{US patent|123456|link text}}}}, 1967).<ref>United States Patent No. 4551552: Process for preparing rimantadine</ref><ref>Template:Cite journal</ref> Prichard's methods of synthesis of rimantadine from the corresponding ketone oxime were based on its reduction with lithium aluminum hydride.Template:Citation needed

See also

• Adapromine
• Bromantane
• Memantine
• Tromantadine

External links

• U.S. FDA press release announcing rimantadine's approval
• U.S. Center for Drug Evaluation and Research rimantadine description
• U.S. NIH rimantadine description
• U.S. CDC flu anti-viral treatment information