Clinical data | |
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Trade names | Gocovri, Symadine, Symmetrel, others |
Other names | 1-Adamantylamine |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682064 |
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Routes of administration | By mouth |
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Pharmacokinetic data | |
Bioavailability | 86–90% [1] |
Protein binding | 67% [1] |
Metabolism | Minimal (mostly to acetyl metabolites) [1] |
Elimination half-life | 10–31 hours [1] |
Excretion | Urine [1] |
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ECHA InfoCard | 100.011.092 |
Chemical and physical data | |
Formula | C10H17N |
Molar mass | 151.253 g·mol−1 |
3D model (JSmol) | |
Melting point | 180 °C (356 °F) [6] |
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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 of widespread drug resistance. [7] [8] It acts as a nicotinic antagonist, dopamine agonist, and noncompetitive NMDA antagonist. [9] [1] The antiviral mechanism of action is antagonism of the influenzavirus A M2 proton channel, which prevents endosomal escape (i.e., the release of viral genetic material into the host cytoplasm). [10] [11]
Amantadine was first used for the treatment of influenza A. After antiviral properties were initially reported in 1963, amantadine received approval for prophylaxis against the influenza virus A in 1976. [12] In 1973, the Food and Drug Administration (FDA) approved amantadine for use in the treatment of Parkinson's disease. In 2017, the extended release formulation was approved for use in the treatment of levodopa-induced dyskinesia. [13]
Amantadine has a mild side-effect profile. Common neurological side effects include drowsiness, light-headedness, dizziness, and confusion. [14] Because of its effects on the central nervous system, it should only be combined cautiously with additional CNS stimulants or anticholinergic drugs. Amantadine is contraindicated in persons with end stage kidney disease, given that the drug is cleared by the kidneys. [5] It should also be taken with caution by those with enlarged prostates or glaucoma, because of its anticholinergic effects. [15]
Amantadine (brand names Gocovri, Symadine, and Symmetrel [1] [16] ) is the organic compound 1-adamantylamine or 1-aminoadamantane, which consists of an adamantane backbone with an amino group substituted at one of the four tertiary carbons. [17] Rimantadine is a closely related adamantane derivative with similar biological properties; [18] both target the M2 proton channel of influenza A virus. [9]
The mechanism of its antiparkinsonian effect is poorly understood. [19] Amantadine is a weak antagonist of the NMDA-type glutamate receptor, increases dopamine release, and blocks dopamine reuptake. [20] [21] [22] Amantadine probably does not inhibit monoamine oxidase (MAO) enzyme. [23] Moreover, the drug has many effects in the brain, including release of dopamine and norepinephrine from nerve endings. It appears to be an anticholinergic (specifically at alpha-7 nicotinic receptors) like the similar pharmaceutical memantine. [24]
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. [24] There has been speculation that these findings may also extend to the other adamantanes such as adapromine, rimantadine, and bromantane, and could explain the psychostimulant-like effects of this family of compounds, but there does not seem to be any evidence available now regarding this theory. [24] [ verification needed ]
The mechanisms for amantadine's antiviral and antiparkinsonian effects are unrelated. [1] [15] Amantadine targets the influenza A M2 ion channel protein. The M2 protein's function is to allow the intracellular virus to replicate (M2 also functions as a proton channel for hydrogen ions to cross into the vesicle), and exocytose newly formed viral proteins to the extracellular space (viral shedding). By blocking the M2 channel, the virus is unable to replicate because of impaired replication, protein synthesis, and exocytosis. [26]
Amantadine and rimantadine function in a mechanistically identical fashion, entering the barrel of the tetrameric M2 channel and blocking pore function—i.e., proton translocation. [9]
Resistance to the drug class is a consequence of mutations to the pore-lining amino acid residues of the channel, preventing both amantadine and rimantadine from binding and inhibiting the channel in their usual way. [27]
Amantadine is well absorbed orally. The onset of action is usually within 48 hours when used for parkinsonian syndromes, including dyskinesia. As plasma concentrations of amantadine increase, there is a greater risk for toxicity. [28] [29]
Half-life elimination averages eight days in patients with end-stage kidney disease. Amantadine is only minimally removed by hemodialysis. [29] [30]
Amantadine is metabolized to a small extent (5–15%) by acetylation. It is mainly excreted (90%) unchanged in urine by kidney excretion. [28]
Amantadine is used to treat Parkinson's disease-related dyskinesia and drug-induced parkinsonism syndromes. [31] Amantadine may be used alone or in combination with another anti-Parkinson's or anticholinergic drug. [9] The specific symptoms targeted by amantadine therapy are dyskinesia and rigidity. [31] The extended release amantadine formulation is commonly used to treat dyskinesias in people receiving levodopa therapy for Parkinson's disease. [31] A 2003 Cochrane review had concluded there was insufficient evidence to prove the safety or efficacy of amantadine to treat dyskinesia. [32]
In 2008, the World Health Organization reported amantadine is not effective as a stand-alone parkinsonian therapy, but recommended it could be used in combination therapy with levodopa. [33]
Amantadine is not recommended for treatment or prophylaxis of influenza A in the United States. [7] Amantadine has no effect preventing or treating influenza B infections. [7] The US Centers for Disease Control and Prevention found 100% of seasonal H3N2 and 2009 pandemic flu samples were resistant to adamantanes (amantadine and rimantadine) during the 2008–2009 flu season. [9] [34]
The U.S. Centers for Disease Control and Prevention (CDC) guidelines recommend only neuraminidase inhibitors for influenza treatment and prophylaxis.[ medical citation needed ] The CDC recommends against amantadine and rimantadine to treat influenza A infections. [7]
Similarly, the 2011 World Health Organization (WHO) virology report showed all tested H1N1 influenza A viruses were resistant to amantadine. [8] WHO guidelines recommend against use of M2 inhibitors for influenza A.[ medical citation needed ] The continued high rate of resistance observed in laboratory testing of influenza A has reduced the priority of M2 resistance testing.[ medical citation needed ]
A 2014 Cochrane review did not find evidence for efficacy or safety of amantadine used for the prevention or treatment of influenza A. [35]
An extended release formulation is used to treat levodopa-induced dyskinesia in patients with Parkinson's disease. [4] The WHO recommends the use of amantadine as a combination therapy to reduce levodopa side effects. [33]
A 2007 Cochrane literature review concluded that there was no overall evidence supporting the use of amantadine in treating fatigue in patients with MS. [36] A follow-up 2012 Cochrane review stated that there may be some amantadine-induced improvement in fatigue in some people with MS. [37] Despite multiple control trials that have also demonstrated improvements in subjective and objective ratings of fatigue, there is no final conclusion regarding its effectiveness. [38]
Consensus guidelines from the German Multiple Sclerosis Society (GMSS) in 2006 state that amantadine produces moderate improvement in subjective fatigue, problem solving, memory, and concentration. Thus, in 2006, GMSS guidelines recommended the use of amantadine in MS-related fatigue. [39]
In the UK NICE recommends considering amantadine for MS fatigue. [40]
Disorders of consciousness (DoC) include coma, vegetative state (VS), and minimally conscious state (MCS). Amantadine has been shown to increase the rate of emergence from a MCS, defined by consistent demonstration of interactive communication and functional objective use. In traumatic brain injury patients in the intensive care unit, amantadine has also been shown in various randomized control trials to increase the rate of functional recovery and arousal, particularly in the time period immediately following an injury. [41] There are also reports of significantly improved consciousness in patients treated for non-traumatic cases of DoC, such as in the case of a subarachnoid hemorrhage, cerebral hemorrhage, and hypoxic encephalopathy. [42] In 2018 the American Academy of Neurology (AAN) updated treatment guidelines on the use of amantadine for patients with prolonged DoC, recommending the use of amantadine (100–200 mg bid) for adults with DoC 4–16 weeks post injury to support early functional recovery and reduce disability. [43]
In various studies, amantadine and memantine have been shown to accelerate the rate of recovery from a brain injury. [44] [45] The time-limited window following a brain injury is characterized by neuroplasticity, or the capacity of neurons in the brain to adapt and compensate after injury. Thus, physiatrists will often start patients on amantadine as soon as impairments are recognized. There are also case reports showing improved functional recovery with amantadine treatment occurring years after the initial brain injury. [41] There is insufficient evidence to determine if the functional gains are a result of effects through the dopamine or norepinephrine pathways. Some patients may benefit from direct dopamine stimulation with amantadine, while others may benefit more from other stimulants that act more on the norepinephrine pathway, such as methylphenidate. [41] It is unclear if treatment with amantadine improves long-term outcomes or simply accelerates recovery. [44] Nonetheless, amantadine-induced acceleration of recovery reduces the burden of disability, lessens health care costs, and minimizes psychosocial stressors in patients.[ citation needed ]
A 2010 randomized clinical trial showed similar improvements in ADHD symptoms in children treated with amantadine as in those treated with methylphenidate, with less frequent side effects. [46] A 2021 retrospective study showed that amantadine may serve as an effective adjunct to stimulants for ADHD–related symptoms and appears to be a safer alternative to second- or third-generation antipsychotics. [47]
Amantadine is generally well tolerated and has a mild side-effect profile. [48]
Side effects include drowsiness (especially while driving), lightheadedness, falls, and dizziness. [4] Patients on amantadine should avoid combination with other central nervous system (CNS) depressing agents, such as alcohol. Excessive alcohol usage may increase the potential for CNS effects such as dizziness, confusion, and light headedness. [14]
Rare severe adverse effects include neuroleptic malignant syndrome, depression, convulsions, psychosis, and suicidal ideation. [14] It has also been associated with disinhibited actions (gambling, sexual activity, spending, other addictions) and diminished control over compulsions. [4]
Amantadine may cause anxiety, feeling overexcited, hallucinations and nightmares. [49]
Amantadine may cause orthostatic hypotension, syncope, and peripheral edema. [4]
Amantadine has also been associated with dry mouth and constipation. [4]
Rare cases of skin rashes, such as Stevens–Johnson syndrome and livedo reticularis have also been reported in patients treated with amantadine. [50] [51]
Amantadine inhibits the kidney's active-transport removal and transfer of creatinine from blood to urine, which normally occurs in the proximal tubules of the nephrons. The active-transport removal mechanism accounts for about fifteen percent of creatinine clearance. Therefore, amantadine may increase serum creatinine concentrations fifteen percent above normal levels and give the false impression of mild kidney disease in patients whose kidneys are actually undamaged (because kidney function is often assessed by measuring the concentration of creatinine in blood.) Also, if the patient does have kidney disease, amantadine may cause it to appear as much as fifteen percent worse than it actually is. [52]
Amantadine is Food and Drug Administration category C for pregnancy. Teratogenic effects have been observed in humans (case reports) and animal reproduction studies. Amantadine may also be present in breast milk and negatively alter breast milk production or excretion. The decision to breastfeed during amantadine therapy should consider the risk of infant exposure, the benefits of breastfeeding, and the benefits of the drug to the mother. [14]
Amantadine may affect the central nervous system because of its dopaminergic and anticholinergic properties. The mechanisms of action are not fully known. Because of the CNS effects, caution is required when prescribing additional CNS stimulants or anticholinergic drugs. [15] Thus, concurrent use of alcohol with Amantadine is not recommended because of enhanced CNS depressant effects. [53] In addition, anti-dopaminergic drugs such as metoclopramide and typical anti-psychotics should be avoided. [54] [55] These interactions are likely related to opposing dopaminergic mechanisms of action, which inhibits amantadine's anti-Parkinson effects.[ medical citation needed ]
Amantadine is contraindicated in persons with end stage kidney disease. [4] The drug is renally cleared. [1] [15] [56]
Amantadine may have anticholinergic side effects. Thus, patients with an enlarged prostate or glaucoma should use with caution. [14]
Live attenuated vaccines are contraindicated while taking amantadine. [4] It is possible that amantadine will inhibit viral replication and reduce the efficacy of administered vaccines. The U.S. Food and Drug Administration recommends avoiding amantadine for two weeks prior to vaccine administration and 48 hours afterward. [15]
Antiviral properties were first reported in 1963 at the University of Illinois Hospital in Chicago. In this amantadine trial study volunteer college students were exposed to a viral challenge. The group that received amantadine (100 milligrams 18 hours before viral challenge) had less Asia influenza infections than the placebo group. [12] Amantadine received approval for the treatment of influenza virus A [57] [58] [59] [60] in adults in 1976. [12] It was first used in West Germany in 1966. Amantadine was approved by the U.S. Food and Drug Administration in October 1968, as a prophylactic agent against Asian (H2N2) influenza and received approval for prophylactic use for influenza A in 1976. [12] [5] [61]
During the 1980 influenza A epidemic, the first amantadine-resistance influenza viruses were reported. The frequency of amantadine resistance among influenza A (H3N2) viruses from 1991 and 1995 was as low as 0.8%. In 2004 the resistance frequency increased to 12.3%. A year later resistance increase significantly to 96%, 72%, and 14.5% in China, South Korea, and the United States, respectively. By 2006, 90.6% of H3N2 strains and 15.6% of H1N1 were amantadine-resistant. A majority of the amantadine-resistant H3N2 isolates (98.2%) were found to contain an S31N mutation in the M2 transmembrane domain that confers resistance to amantadine. [62] Currently, adamantane resistance is high among circulating influenza A viruses. Thus, they are no longer recommended for treatment of influenza A. [63]
An incidental finding in 1969 prompted investigations about amantadine's effectiveness for treating symptoms of Parkinson's disease. [12] A woman with Parkinson's disease was prescribed amantadine to treat her influenza infection and reported her cogwheel rigidity and tremors improved. She also reported that her symptoms worsened after she finished the course of amantadine. [12] The published case report was not initially corroborated by any other instances by the medical literature or manufacturer data. A team of researchers looked at a group of ten patients with Parkinson's disease and gave them amantadine. Seven of the ten patients showed improvement, which was convincing evidence for the need of a clinical trial, which included 163 patients with Parkinson's disease and 66% experienced subjective or objective reduction of symptoms with a maximum daily dose of 200 mg. [12] [64] Additional studies followed patients for greater lengths of time and in different combinations of neurological drugs. [65] It was found to be a safe drug that could be used over long periods of time with few side effects as monotherapy or in combination with L-dopa or anti-cholinergic drugs. [12] By April 1973, the U.S. Food and Drug Administration approved amantadine for use in the treatment of Parkinson's disease. [15] [12]
In 2017, the U.S. Food and Drug Administration approved the use of amantadine in an extended release formulation for the treatment of dyskinesia, an adverse effect of levodopa in people with Parkinson's disease. [66] [67]
In 2005, Chinese poultry farmers were reported to have used amantadine to protect birds against avian influenza. [68] In Western countries and according to international livestock regulations, amantadine is approved only for use in humans. Chickens in China have received an estimated 2.6 billion doses of amantadine. [68] Avian flu (H5N1) strains in China and southeast Asia are now resistant to amantadine, although strains circulating elsewhere still seem to be sensitive. If amantadine-resistant strains of the virus spread, the drugs of choice in an avian flu outbreak will probably be restricted to neuraminidase inhibitors oseltamivir and zanamivir which block the action of viral neuraminidase enzyme on the surface of influenza virus particles. [62] However, there is an increasing incidence of oseltamivir resistance in circulating influenza strains (e.g., H1N1), highlighting the need for new anti-influenza therapies. [69]
In September 2015, the U.S. Food and Drug Administration announced the recall of Dingo Chip Twists "Chicken in the Middle" dog treats because the product has the potential to be contaminated with amantadine. [70]
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, a larger group which also includes antibiotic, antifungal and antiparasitic drugs, or antiviral drugs based on monoclonal antibodies. Most antivirals are considered relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from virucides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Natural virucides are produced by some plants such as eucalyptus and Australian tea trees.
Benzatropine (INN), known as benztropine in the United States and Japan, is a medication used to treat movement disorders like parkinsonism and dystonia, as well as extrapyramidal side effects of antipsychotics, including akathisia. It is not useful for tardive dyskinesia. It is taken by mouth or by injection into a vein or muscle. Benefits are seen within two hours and last for up to ten hours.
l-DOPA, also known as levodopa and l-3,4-dihydroxyphenylalanine, is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize l-DOPA, make it via biosynthesis from the amino acid l-tyrosine. l-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Furthermore, l-DOPA itself mediates neurotrophic factor release by the brain and CNS. In some plant families, l-DOPA is the central precursor of a biosynthetic pathway that produces a class of pigments called betalains. l-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Pharmacopa, Atamet, and Stalevo. As a drug, it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.
Zanamivir is a medication used to treat and prevent influenza caused by influenza A and influenza B viruses. It is a neuraminidase inhibitor and was developed by the Australian biotech firm Biota Holdings. It was licensed to Glaxo in 1990 and approved in the US in 1999, only for use as a treatment for influenza. In 2006, it was approved for prevention of influenza A and B. Zanamivir was the first neuraminidase inhibitor commercially developed. It is marketed by GlaxoSmithKline under the trade name Relenza as a powder for oral inhalation.
Oseltamivir, sold under the brand name Tamiflu, is an antiviral medication used to treat and prevent influenza A and influenza B, viruses that cause the flu. Many medical organizations recommend it in people who have complications or are at high risk of complications within 48 hours of first symptoms of infection. They recommend it to prevent infection in those at high risk, but not the general population. The Centers for Disease Control and Prevention (CDC) recommends that clinicians use their discretion to treat those at lower risk who present within 48 hours of first symptoms of infection. It is taken by mouth, either as a pill or liquid.
Rimantadine 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 (FDA) in 1994.
Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor of the hands to an uncontrollable movement of the upper body or lower extremities. Discoordination can also occur internally especially with the respiratory muscles and it often goes unrecognized. Dyskinesia is a symptom of several medical disorders that are distinguished by their underlying cause.
Punding is compulsive performance of repetitive, mechanical tasks, such as assembling and disassembling, collecting, or sorting objects. It can also apply to digital objects, such as computer files and data. The term was originally coined to describe complex, prolonged, purposeless, and stereotyped behaviour in phenmetrazine and chronic amphetamine users, by Swedish forensic psychiatrist G. Rylander, in 1968. It was later described in Parkinson's disease, but mainly in cases of patients being treated with dopaminergic drugs. It has also been described in methamphetamine and cocaine users, as well as in some patients with gambling addictions, and hypersexuality.
The Matrix-2 (M2) protein is a proton-selective viroporin, integral in the viral envelope of the influenza A virus. The channel itself is a homotetramer, 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.
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.
Extrapyramidal symptoms (EPS) are symptoms that are archetypically associated with the extrapyramidal system of the brain's cerebral cortex. When such symptoms are caused by medications or other drugs, they are also known as extrapyramidal side effects (EPSE). The symptoms can be acute (short-term) or chronic (long-term). They include movement dysfunction such as dystonia, akathisia, parkinsonism characteristic symptoms such as rigidity, bradykinesia, tremor, and tardive dyskinesia. Extrapyramidal symptoms are a reason why subjects drop out of clinical trials of antipsychotics; of the 213 (14.6%) subjects that dropped out of one of the largest clinical trials of antipsychotics, 58 (27.2%) of those discontinuations were due to EPS.
In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutrition. At present, no cure for the disease is known, but medications or surgery can provide relief from the symptoms.
Istradefylline, sold under the brand name Nourianz, is a medication used as an add-on treatment to levodopa/carbidopa in adults with Parkinson's disease (PD) experiencing "off" episodes. Istradefylline reduces "off" periods resulting from long-term treatment with the antiparkinson drug levodopa. An "off" episode is a time when a patient's medications are not working well, causing an increase in PD symptoms, such as tremor and difficulty walking.
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.
Parkinson's disease (PD), or simply Parkinson's, is a chronic degenerative disorder of the central nervous system that affects both the motor system and non-motor systems. The symptoms usually emerge slowly, and as the disease progresses, non-motor symptoms become more common. Early symptoms are tremor, rigidity, slowness of movement, and difficulty with walking. Problems may also arise with cognition, behaviour, sleep, and sensory systems. Parkinson's disease dementia is common in advanced stages.
Befiradol is an experimental drug being studied for the treatment of levodopa-induced dyskinesia. It is a potent and selective 5-HT1A receptor full agonist.
Levodopa-induced dyskinesia (LID) is a form of dyskinesia associated with levodopa (l-DOPA), used to treat Parkinson's disease. It often involves hyperkinetic movements, including chorea, dystonia, and athetosis.
Favipiravir, sold under the brand name Avigan among others, is an antiviral medication used to treat influenza in Japan. It is also being studied to treat a number of other viral infections, including SARS-CoV-2. Like the experimental antiviral drugs T-1105 and T-1106, it is a pyrazinecarboxamide derivative.
Adapromine is an antiviral drug of the adamantane group related to amantadine (1-aminoadamantane), rimantadine, 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.
Viroporins are small and usually hydrophobic multifunctional viral proteins that modify cellular membranes, thereby facilitating virus release from infected cells. Viroporins are capable of assembling into oligomeric ion channels or pores in the host cell's membrane, rendering it more permeable and thus facilitating the exit of virions from the cell. Many viroporins also have additional effects on cellular metabolism and homeostasis mediated by protein-protein interactions with host cell proteins. Viroporins are not necessarily essential for viral replication, but do enhance growth rates. They are found in a variety of viral genomes but are particularly common in RNA viruses. Many viruses that cause human disease express viroporins. These viruses include hepatitis C virus, HIV-1, influenza A virus, poliovirus, respiratory syncytial virus, and SARS-CoV.