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 accomm ...

, sold under the trade name Flumadine) is an orally administered

antiviral drug Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Antiviral drugs are a class of antimicrobials ...

used to treat, and in rare cases prevent,

influenzavirus A ''Influenza A virus'' (''Alphainfluenzavirus influenzae'') or IAV is the only species of the genus ''Alphainfluenzavirus'' of the virus family '' Orthomyxoviridae''. It is a pathogen with strains that infect birds and some mammals, as well as c ...

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 Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended because ...

are derivates of

adamantane Adamantane is an organic compound with formula C10H16 or, more descriptively, (CH)4(CH2)6. Adamantane molecules can be described as the fusion of three cyclohexane rings. The molecule is both rigid and virtually stress-free. Adamantane is the mo ...

. 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 List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(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 uses

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 over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

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 ...

, 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 (electrophysiol ...

specified by virion M2

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

, 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 In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

mixture; the R and S states are both present in the drug. Solid state

NMR Nuclear magnetic resonance (NMR) is a physical phenomenon in which atomic nucleus, nuclei in a strong constant magnetic field are disturbed by a weak oscillating magnetic field (in the near and far field, near field) and respond by producing ...

studies have shown that the R

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

has a stronger binding affinity to the M2 channel pore than the S-enantiomer of rimantadine. Antiviral assay and

electrophysiology Electrophysiology (from ee the Electron#Etymology, etymology of "electron" ; and ) is the branch of physiology that studies the electrical properties of biological cell (biology), cells and tissues. It involves measurements of voltage change ...

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

, possesses antiparkinsonian activity and can be used in the treatment of

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

. 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.

Others

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 Transmission (medicine), transmitted by arthropod Vector (epidemiology), vectors. The term ''arbovirus'' is a portmanteau word (''ar''thropod-''bo''rne ''virus''). ''Tibovirus'' (''ti''ck-''bo ...

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 Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include ...

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 tract is the largest of the body's systems, after the cardiovascular system. ...

and

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

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 complic ...

. 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. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

* Upset stomach *

Nervousness Anxiety is an emotion characterised by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different from fear in that fear is defined as the emotional response to a present threat, where ...

* Tiredness *

Lightheadedness Lightheadedness is a common and typically unpleasant sensation of dizziness or a feeling that one may faint. The sensation of lightheadedness can be short-lived, prolonged, or, rarely, recurring. In addition to dizziness, the individual may fee ...

* Trouble sleeping (

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

) * Difficulty concentrating * Confusion Rimantadine shows fewer CNS symptoms than its sister drug amantadine.

Interactions

* Taking

paracetamol Paracetamol, or acetaminophen, is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. It is a widely available over-the-counter drug sold under various brand names, including Tylenol and Panadol. Parac ...

(acetaminophen, Tylenol) or

acetylsalicylic acid Aspirin () is the Generic trademark, genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions ...

(aspirin) while taking rimantadine is known to reduce the body's uptake of rimantadine by approximately 12%. *

Cimetidine Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers. With the development of proton pump ...

also affects the body's uptake of rimantadine. * Taking anticholinergic drugs with amantadine may increase underlying seizure disorders and aggravate congestive heart failure.

Pharmacology

Pharmacodynamics

The related drugs

memantine Memantine, sold under the brand name Namenda among others, is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth. Common side effects include headache, constipation, sleepiness, and dizz ...

and to a much lesser extent

are known to act as

NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to receptor antagonist, antagonize, or inhibit the action of, the NMDA, ''N''-Methyl-D-aspartate receptor (NMDA receptor, NMDAR). They are commonly used as anesthetics for humans and anima ...

s. The

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

of rimantadine for the

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...

does not seem to have been reported. Analogues of rimantadine are known to act as NMDA receptor antagonists.

Chemistry

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 is the List of municipalities in Delaware, most populous city in the U.S. state of Delaware. The city was built on the site of Fort Christina, the first Swedish colonization of the Americas, Swedish settlement in North America. It lie ...

(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.

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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Pharmacodynamics Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...

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