Rimantadine (INN, sold under the trade nameFlumadine[1]) is an orally administeredantiviral drug[2] 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.[3] Both rimantadine and the similar drugamantadine are derivates ofadamantane. Rimantadine is found to be more effective than amantadine because when used the patient displays fewer symptoms.[4] Rimantadine was approved by theFood and Drug Administration (FDA) in 1994.
Rimantadine was approved for medical use in 1993.[5] Seasonal H3N2 and2009 pandemic flu samples tested have shown resistance to rimantadine, and it is no longer recommended to prescribe for treatment of the flu.[6]
Rimantadine inhibits influenza activity by binding toamino acids in theM2 transmembrane channel and blocking proton transport across the M2 channel.[7] Rimantadine is believed to inhibit influenza'sviral replication, possibly by preventing the uncoating of the virus's protective shells, which are theenvelope and capsid. The M2 channel is known to be responsible for viral replication in the influenza virus. Genetic studies suggest that the virusM2 protein, anion channel specified by virion M2gene, plays an important role in the susceptibility of influenza A virus to inhibition by rimantadine.[citation needed]
Rimantadine is bound inside the pore to amantadine specific amino acid binding sites with hydrogen binding and van der Waals interactions.[8] 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.[citation needed]
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.[9]
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).[citation needed]
Rimantadine, when sold as flumadine, is present as aracemic mixture; the R and S states are both present in the drug. Solid stateNMR studies have shown that the Renantiomer has a stronger binding affinity to the M2 channel pore than the S-enantiomer of rimantadine.[10]Antiviral assay andelectrophysiology studies show that there is no significant difference between the R and S enantiomers in binding affinity to amino acids in the M2 channel.[11] Since the enantiomers have similar binding affinity, they also have similar ability to block the channel pore and work as an effective antiviral.[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.[citation needed]
Rimantadine, like its antiviral cousinamantadine, possessesantiparkinsonian activity and can be used in the treatment ofParkinson's disease.[12][13] 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 tofront-line treatments.[citation needed]
Takingparacetamol (acetaminophen, Tylenol) oracetylsalicylic acid (aspirin) while taking rimantadine is known to reduce the body's uptake of rimantadine by approximately 12%.[18]
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.[26]
The synthesis pictured to the left is a synthesis of rimantadine as synthesized in Europe.[citation needed]
Rimantadine was discovered in 1963[27][28] and patented in 1965 in the US by William W. Prichard inDu Pont & Co.,Wilmington, Delaware (patent on new chemical compoundU.S. patent 3,352,912, 1965 and on the first method of synthesisU.S. patent 3,592,934, 1967).[29][30] Prichard's methods of synthesis of rimantadine from the corresponding ketone oxime were based on its reduction with lithium aluminum hydride.[citation needed]
^Evidente VG, Adler CH, Caviness JN, Gwinn-Hardy K (1999). "A pilot study on the motor effects of rimantadine in Parkinson's disease".Clin Neuropharmacol.22 (1):30–32.doi:10.1097/00002826-199901000-00006.PMID10047931.
^Singer C, Papapetropoulos S, Gonzalez MA, Roberts EL, Lieberman A (July 2005). "Rimantadine in Parkinson's disease patients experiencing peripheral adverse effects from amantadine: report of a case series".Mov Disord.20 (7):873–877.doi:10.1002/mds.20471.PMID15809995.
^Zlydnikov DM, Kubar OI, Kovaleva TP, Kamforin LE (1981-05-01). "Study of rimantadine in the USSR: a review of the literature".Reviews of Infectious Diseases.3 (3):408–21.doi:10.1093/clinids/3.3.408.PMID7025146.
^Younossi ZM, Perrillo RP (1999). "The roles of amantadine, rimantadine, ursodeoxycholic acid, and NSAIDs, alone or in combination with alpha interferons, in the treatment of chronic hepatitis C".Seminars in Liver Disease.19 (Suppl 1):95–102.PMID10349697.
^Manchand PS, Cerruti RL, Martin JA, Hill CH, Merrett JH, Keech E, et al. (July 1990). "Synthesis and antiviral activity of metabolites of rimantadine".Journal of Medicinal Chemistry.33 (7):1992–5.doi:10.1021/jm00169a029.PMID2362279.
^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.
^Zlydnikov DM, Kubar OI, Kovaleva TP, Kamforin LE (1981). "Study of rimantadine in the USSR: a review of the literature".Reviews of Infectious Diseases.3 (3):408–21.doi:10.1093/clinids/3.3.408.PMID7025146.
