Amantadine antiviral activity

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]. 

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... 

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. 

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). 

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

The effects of antiviral chemotherapeutic agents such as cyclosporin A, benzyloxy-carbonyl-D-Phe-L-Phe-Gly, and amantadine on membrane properties have been studied using the combination of 31P-NMR and DSC. It was found that benzyloxycar-bonyl-D-Phe-L-Phe-Gly was most effective in raising the bilayer to Hn phase transition temperature. Cyclosporin A caused the greatest broadening of the 31P-NMR signal. It was suggested that both effects are related to the inhibitory activity on membrane fusion and possibly also to their antiviral activity [151]. 

AMANTADINE is used to treat Parkinson s disease as well as having antiviral activity. It has been included in the antiparkinson s drugs section ... 

Amantadine is a symmetrical CIO tricyclic amine with an unusual structure (1-adamantanamine hydrochloride). It interferes with virus uncoating (1) by blocking the M2 ion channel, which is needed to affect a pH change that helps to initiate the uncoating process. Most consistent antiviral activity has been observed against influenza A virus, but amantadine has httle or no activity against influenza B virus (2). However, influenza A virus can become rapidly resistant to amantadine in vitro (3). Amantadine also promotes the release of dopamine from nerve endings, but may also delay its reuptake into synaptic vesicles. 

Oxford JS, Galbraith A. Antiviral activity of amantadine a review of laboratory and clinical data. Pharmacol Ther 1980 ll(l) 181-262. 

Apart from the amantadines (section 14.1) and me-thisazone (section 14.2), various non-nucleoside drugs have shown antiviral activity. Two simple molecules with potent activity are phosphonoacetic... 

Rimatadine is structurally similar to amantadine, and has a similar spectrum of antiviral activity. No nephrotoxicity has been described with rimatadine. 

Oseltamivir phosphate is an ethyl ester prodrug that lacks antiviral activity. Oseltamivir carboxylate has an antiviral spectrum and potency similar to that of zanamivir. It inhibits amantadine- and rimantadine-resistant influenza A viruses and some zanamivir-resistant variants. 

CHEMISTRY AND ANTIVIRAL ACTIVITY Amantadine (1-adamantanamine hydrochloride) and its a-methyl derivative rimantadine (a-methyl-l-adamantane methylamine hydrochloride) are tricyclic amines. 

CHEMISTRY AND ANTIVIRAL ACTIVITY Zanamivir (4-guanidino-2,4-dideoxy-2, 3-dehydro-/V-acetyl neuraminic acid) is a siaMc acid analog that potently and specifically inhibits the neuraminidases of influenza A and B viruses. Depending on the strain, zanamivir competitively inhibits influenza neuraminidase activity but affects neuraminidases from other pathogens and mammalian sources only at much higher concentrations. Zanamivir inhibits in vitro replication of influenza A and B viruses, including amantadine- and rimantadine-resistant strains and several oseltamivir-resistant variants. 

Cyclooctylamlne HCl demonstrated antiviral activity against a variety of myxovlruses as well as IBR, herpes zoster and vaccinia in tissue culture and against influenza kl/kk/z/bO and A/Swine/sl5 but not a/fR8 in mlce. Other amine and ammonium compounds were found to be effective against influenza A viruses in mammalian cells as measured by a quantitative immunofluorescent technic with a mechanism similar to that of amantadine HCl. 

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). 

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. 

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... 

Figure 13.8. Chemical structure of amantadine and of centrally acting anticholinergic agents used in the treatment of Parkinsonism. The antiviral compound amantadine is a dopamine-releasing agent with some anticholinergic activity.

Amantadine The antiviral efficacy of amantadine was first reported by w. Davies et al. in 1964. The mode of action consists in preventing uncoating and viral maturation (inhibition of the release of the nucleic acids that have already penetrated the host cell). The active substance is almost completely absorbed following oral intake. It is eliminated unchanged via the kidneys. Half-life is about 16 hours. So far, it has been used to combat influenza virus type A. Tolerance is good. Amantadine on its own is only minimally effective against HCV it is therefore not suitable for initial monotherapy. 

Amantadine and rimantadine are chemically related antiviral drugs active against influenza A but not influenza B viruses. Amantadine differs from rimantadine because it is primarily renally eliminated and is associated with more CNS side effects and can potentially lower the seizure threshold. 

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