Rimantadine (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

, sold under the trade name '
Flumadine
'') is an orally administered antiviral drug 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. 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. Rimantadine was approved by the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) in 1994. Rimantadine was approved for medical use in 1993. 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.

Medical use

Influenza A

Rimantadine inhibits influenza activity by binding to

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

s in the M2 transmembrane channel and blocking proton transport across the M2 channel. Rimantadine is believed to inhibit influenza's

viral replication Viral replication is the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. Through the generation of abundant copies of its genome a ...

, 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 Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...

specified by virion M2

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

, plays an important role in the susceptibility of influenza A virus to inhibition by rimantadine. Rimantadine is bound inside the pore to amantadine specific amino acid binding sites with hydrogen binding and van der Waals interactions. 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. 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. 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).

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 In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...

has a stronger binding affinity to the M2 channel pore than the S-enantiomer of rimantadine. 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. Since the enantiomers have similar binding affinity, they also have similar ability to block the channel pore and work as an effective antiviral. 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.

Parkinson's disease

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 Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

). 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.

Other

Rimantadine is shown to be effective against other RNA-containing viruses. It can treat

arbovirus Arbovirus is an informal name for any virus that is transmitted by arthropod vectors. The term ''arbovirus'' is a portmanteau word (''ar''thropod-''bo''rne ''virus''). ''Tibovirus'' (''ti''ck-''bo''rne ''virus'') is sometimes used to more spe ...

es like Saint Louis encephalitis and Sindbis. Other viruses that can be treated with Rimantadine include respiratory synctial and parainfluenza viruses. Rimantadine has also been shown to treat chronic hepatitis C.

Drug interactions

* Taking

paracetamol Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol. At a standard dose, paracetamol only slightly decreases body temperature; it is inferi ...

(acetaminophen, Tylenol) or acetylsalicylic acid (aspirin) while taking rimantadine is known to reduce the body's uptake of rimantadine by approximately 12%. * Cimetidine also affects the body's uptake of rimantadine. * Taking anticholigenic drugs with amantadine may increase underlying seizure disorders and aggravate congestive heart failure.

Side effects

Rimantadine can produce

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

and

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

adverse effects An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a " side effect", when judged to be secondary to a main or therapeutic effect. The term compl ...

. Approximately 6% of patients (compared to 4% of patients taking a placebo) reported side-effects at a dosage of 200 mg/d. Common side effects include: *

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

* upset stomach * nervousness * tiredness * lightheadedness * trouble sleeping (

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy ...

) * difficulty concentrating * confusion *

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil Turmoil may refer to: * ''Turmoil'' (1984 video game), a 1984 video game released by Bug-Byte * ''Turmoil'' (2016 video game), a 2016 indie oil tycoon video ...

Rimantadine shows fewer CNS symptoms than its sister drug Amantadine. Rimantadine synthesis 1

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. The synthesis pictured to the left is a synthesis of rimantadine as synthesized in Europe

History

Rimantadine was discovered in 1963 and patented in 1965 in the US by William W. Prichard in Du Pont & Co.,

Wilmington, Delaware Wilmington (Lenape: ''Paxahakink /'' ''Pakehakink)'' is the largest city in the U.S. state of Delaware. The city was built on the site of Fort Christina, the first Swedish settlement in North America. It lies at the confluence of the Christin ...

(patent on new chemical compound , 1965 and on the first method of synthesis , 1967). Prichard's methods of synthesis of rimantadine from the corresponding ketone oxime were based on its reduction with lithium aluminum hydride.

Synonyms

1-(1-Adamantyl)ethanamine, 1-(Adamantan-1-yl)ethanamine, 1-(adamantan-1-yl)ethan-1-aminem, alpha-Methyl-1-adamantanemethylamine, alpha-Methyladamantanemethylamine, Rimantadine NN:BAN Rimantadinum NN-Latin 1-(1-Adamantyl)ethylamin, Remantadine, Rimantadina NN-Spanish 1-Adamantan-1-yl-ethylamine, RIMANTADIN, HSDB 7438, CHEMBL959, BRN 2715740, 1-Adamantanemethylamine, .alpha.-methyl-, .alpha.-Methyladamantanemethylamine, 1-(1-adamantyl)-ethylamine, 1-(tricyclo .3.1.1~3,7~ec-1-yl)ethanamine, Riamantadine, Rimantadina, Rimantadinum, Tricyclo(3.3.1.13,7)decane-1-methanamine, alpha-methyl-, -(1-adamantyl)ethylmine hydrochloride, Tricyclo(3.3.1.1(sup 3,7))decane-1-methanamine, alpha-methyl-, 1-ADAMANTANEMETHYLAMINE, alpha-METHYL-, 1-Rimantadine, 887336-05-2, Tricyclo .3.1.13,7ecane-1-methanamine, a-methyl-, Rimant, 1-(1-adamantyl)ethylamine, Rimantadine (INN), Enamine_005755, NCGC00159491-02, Rimant & .alpha. IFN, Rimantadine (Flumadine), Rimantidine & .alpha.IFN, 1-Adamantan-1-ylethylamine, rimantidin, Rimantadin A, (R)-1-(Adamantan-1-yl)ethan-1-amine, 1-adamantanylethylamine, Maybridge1_002066, SCHEMBL2981, 1-tricyclo .3.1.1~3,7~ec-1-ylethanamine, Oprea1_602732, SCHEMBL2619249, CHEMBL1201272, DTXSID2023561, SCHEMBL20409367, CHEBI:94440, CTK6A4437, HMS1410F13, HMS2090L19, HMS3604N13, HMS3655J05, 1-Adamantanemethylamine, ?-methyl-, ALBB-013870, BCP12269, HY-B0338, ZX-AN012619, ANW-72018, BBL013215, BDBM50216627, MFCD00869344, s1964, STK177253, (alpha-methyl-1-adamantyl)methylamine, AKOS000264537, AKOS006238592, AKOS016038537, .alpha.-Methyl-1-adamantanemethylamine, AM84461, API0024288, BBV-156986, CCG-236078, CS-2380, DB00478, FCH3207896, MCULE-9027470290, IDI1_007990, NCGC00159491-03, NCGC00159491-05, AK-58175, AS-68744, CC-34261, LS-15019, OR315791, SBI-0206810.P001, AB0012750, AX8049536, DB-042207, FT-0630403, H6325, ST45025920, SW220023-1, EN300-33990, C07236, D08483, Q421711- 3R,5S,7s)-adamantan-1-ylthan-1-amine, AB00638368-09, AB00959689-03, AB01506092_02, AB01506092_03, 392R284, C-06592, BRD-A84282119-003-01-2, Z56757137, 1-(Tricyclo .3.1.1>3,7>ec-1-yl)ethanamine (HCl), Tricyclo(3.3.1.1^3,7)decane-1-methanamine, .alpha.-methyl-, 1-(1-Adamantyl)ethylamine Hydrochloride;Rimantadine hydrochloride, Tricyclo(3.3.1.1(sup 3,7))decane-1-methanamine, .alpha.-methyl-, Tricyclo ,3,1,1(3,7)ecane-1-methanamine, .alpha.-methyl-, Tricyclo(3.3.1.1^3,7)decane-1-methanamine, .alpha.-methyl- & IFN.alpha

References

External links

U.S. FDA press release announcing rimantadine's approval

* ttps://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a698029.html U.S. NIH rimantadine description
U.S. CDC flu anti-viral treatment information
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