Antivirals amantadine

Amantadine hydrochloride [665-66-7] (1-adamantanamine hydrochloride, 41), C qH N HQ., (93) is a good example of a narrow-spectmm agent active only against influenza A vims. It became the first antiviral dmg available for systemic use in the United States when it was approved by the FDA in 1966 for use against Asian influenza. In 1976, FDA approval was extended to the use of amantadine for the reHef of symptoms of all influenza A strains. Amantadine is marketed by Du Pont de Nemours Co., Inc. A stmcturaHy related dmg, rimantadine hydrochloride [1501 -84-4] C 2H2 N HQ, (a-methyl-l-adamantanemethylamine hydrochloride, 42), is widely used in Russia to treat influenza A vims (94). 

Amantadine is an antiviral agent that is active against influenza A infection and against some strains of H5NX avian flu. Draw a three-dimensional representation of amantadine showing the chair cyclohexane rings. 

Amantadine is less effective than levodopa in the treatment of Fhrkinson s disease but more effective than die anticholinergics. Amantadine may be given alone or in combination witii an antiparkinsonism drug witii anticholinergic activity. Amantadine is also used as an antiviral drug (see Chap. 14). 

To further improve sustained virologic response rates, different treatment approaches are currently under investigation. For example, individualized therapy durations on the basis of the HCV RNA concentration at baseline and early during therapy are the subject of clinical studies (Berg et al. 2006 Zeuzem et al. 2005a). In addition, triple therapy with other antiviral compounds, such as amantadine, has been evaluated in multiple studies, leading to contradictory results (Mangia et al. 2004). 

In pharmacology, two adamantane derivatives. Amantadine (1-adamanta-neamine hydrochloride) and Rimantadine (a-methyl-1-adamantane methyla-mine hydrochloride) (see Fig. 24), have been well known because of their antiviral activity [129]. The main application of these drugs is prophylaxis (treatment to prevent the onset of a particular disease) and treatment of influenza-A viral infections. They are also used in the treatment of parkinsonism and inhibition of hepatitis-C virus. Memantine (1-amino-3,5-dimethyladaman-tane) (see Fig. 24) has been reported effective in slowing the progression of Alzheimer s disease [130]. 

Albumin. Albumin is available in highly pure and uniform form, and exhibits low toxicity and good biological stability. It has been used as a carrier for methotrexate and a variety of antiviral drugs [amantadine, fioxuridine (5-fluorodeoxyuridine), and cytar-abine (cytosine arabinoside)] to treat macrophage tumors and infections caused by DNA viruses growing in macrophages. Heavily modified albumins are known... 

Amantadine, a synthetic antiviral agent used prophylactically against influenza A2, is thought to act by... 

The two classes of antiviral drugs available for treatment of influenza are the same as those available for prophylaxis and include the adamantanes, amantadine and rimantadine, and the neuraminidase inhibitors, oseltamivir and zanamivir. Because of widespread resistance to the adamantanes among influenza A viruses in the United States, amantadine and rimantadine are not recommended for treatment of influenza until susceptibility can be reestablished. 

Currently, amantadine, vidarabine, trifluridine, idoxuridine, sciclovir, ribavirin, and zidovudine are used as antiviral drugs. An analysis of the mechanisms of action of existing and used viral drugs permits the conclusion to be made that they can increase resistance of... 

Pharmacology Inhibits the replication of influenza A virus isolates from each of the subtypes. Amantadine s antiviral activity is not completely understood. Its mode of action appears to be the prevention of the release of infectious viral nucleic acid P.1044... 

Rimantadine (Flumadine) [Antiviral] Uses Prophylaxis Rx of influenza A viral Infxns but not for HlNl swine flu Action Antiviral Dose Adults Feds >9 y. 100 mg PO bid Feds 2-9 y. 5 mg/kg/d PO, 150 mg/d max daily w/ severe renal/hepatic impair elderly initiate w/in 48 h of Sx onset Caution [C, -] w/ cimetidine avoid w/ PRG, breast-feeding Contra Component amantadine allergy Disp Tabs SE Orthostatic X BP, edema, dizziness, GI upset, X Sz threshold Interactions T Effects W/ cimetidine i effects W/ acetaminophen, ASA EMS Concurrent EtOH usage may result in light-headedness, confusion, syncope, and hypotension OD May cause N/V, tremors, Szs, anticholinergic Sxs, ventricular arrhythmias give IV fluids... 

Currently, two classes of drugs are available with antiviral activity against influenza viruses inhibitors of the ion channel activity of the M2 membrane protein, amantadine and rimantadine, and the neuraminidase inhibitors oseltamivir, and zanamivir. H5N1 viruses isolated from poultry and humans in Thailand and Viet Nam in 2004 invariably showed an amantadine-resistance indicating that amantadine treatment is not an option during the ongoing outb-treak in South-East Asia. 

Amantadine was originally introduced as an antiviral compound (see Chapter 50), but it is modestly effective in treating symptoms of parkinsonism. It is useful in the early stages of parkinsonism or as an adjunct to levodopa therapy. Its mechanism of action in parkinsonism is not clear, but amantadine may affect dopamine release and reuptake. Additional sites of action may include antagonism at muscarinic and A-methyl-D-aspartate (NMDA) receptors. Adverse effects include nausea, dizziness, insomnia, confusion, hallucinations, ankle edema, and livedo reticularis. Amantadine and the anticholinergics may exert additive effects on mental functioning. 

Viral resistance develops rapidly in approximately 30% of individuals treated with amantadine or rimantadine. Resistant viruses are associated with the failure of drug prophylaxis in close contacts of infected individuals who have been treated with these antiviral agents. Mutation in the transmembrane domain of the M2 protein is the most frequent cause of resistance to amantadine and rimantadine. 

The Centers for Disease Control s (CDC) Immunization Practices Advisory Committee recommends annual vaccination as the method of choice in the prevention of influenza infection. However, when vaccination is contraindicated or early vaccination is not possible, amantadine and rimantadine are effective prophylactic agents that have been shown to protect approximately 70 to 90% of patients from influenza A infection. Since these drugs do not prevent the host immune response to influenza A, they may be used to prevent infection during the 2- to 4-week period required to develop immunity following vaccination. An additional use of amantadine, unrelated to its antiviral activity, is in the therapy of Parkinson s disease (see Chapter 31). 

Mechanism of Action A dopaminergic agonist that blocks the uncoating of influenza A virus, preventing penetration into the host and inhibiting M2 protein in the assembly of progeny virions. Amantadine also blocks the reuptake of dopamine into presyn-aptic neurons and causes direct stimulation of postsynaptic receptors. Therapeutic Effect Antiviral and antiparkinsonian activity. 

The storage and release of DA can be modified irreversibly by reserpine (3.1), just as in vesicles containing other catecholamines and serotonin. Dopamine release can be blocked specifically by y-hydroxybutyrate (4.78) or its precursor, butyrolactone, which can cross the blood-brain barrier. High doses of amphetamines do deplete the storage vesicles, but this is not their principal mode of action. Apparently, amantadine (4.79), an antiviral drug that is likewise beneficial in parkinsonism (and also perhaps to relieve fatigue in multiple sclerosis), may also act by releasing DA. 

Amantadine, an antiviral agent, was by chance found to have antiparkinsonism properties. Its mode of action in parkinsonism is unclear, but it may potentiate dopaminergic function by influencing the synthesis, release, or reuptake of dopamine. It has been reported to antagonize the effects of adenosine at adenosine 2 receptors, which are receptors that may inhibit D2 receptor function. Release of catecholamines from peripheral stores has also been documented. 

Phosphonoformate is a pyrophosphate analog and inhibits both DNA polymerases and reverse transcriptase. However, toxicity may prevent longterm treatment of AIDS patients. Amantadine has a narrow antiviral specificity. It specifically inhibits initiation of the replication of influenza virus RNA of type A (but not of type B). Active only against retroviruses, 3 -azidothymidine is a reverse transcriptase inhibitor, which acts by a chain termination mechanism. It was synthesized in the early 1960s but only recently has been used in treatment of AIDS victims. More recently a series of 2, 3 -dideoxynucleosides, such as dideoxyinosine, have also been used.d Acyclic phosphonates, such as phosphonylmethoxypropyladenine, avoid the need for metabolic phosphorylation of the drug.6... 

Mechanism of Action. Amantadine and rimantadine appear to inhibit one of the early steps in influenza A replication by blocking the uncoating of the virus and preventing the release of viral nucleic acid within the host cell.42 These drugs may also interfere with the assembly of viral components, thus inhibiting one of the final steps in the replication process42 This dual inhibitory effect on the early and late steps of viral replication accounts for these drugs antiviral effectiveness. 

Torre F, Campo N, Giusto R, et al. Antiviral activity of amantadine in elderly patients with chronic hepatitis C. Gerontology. 2001 47 330-333. 

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