Amantadine resistance

Abed Y, Goyette N, Boivin G (2005) Generation and characterization of recombinant influenza A (HlNl) viruses harboring amantadine resistance mutations, Antimicrob Agents Chemother 49 556-559... 

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. 

Mast EE, Harmon MW, Gravenstein S, et al. Emergence and possible transmission of amantadine-resistant viruses during nursing home outbreaks of influenza A (H3N2). Am J Epidem 1991 134(9) 988—997. 

The adamantanes, amantadine and rimantadine, are currently not recommended for prophylaxis or treatment in the United States because 92% of the circulating influenza A viruses are resistant to these agents. 

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... 

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. 

In the absence of resistance, both amantadine and rimantadine, at 100 mg twice daily or 200 mg once daily, are 70-90% protective in the prevention of clinical illness when initiated before exposure. When begun within 1-2 days after the onset of illness, the duration of fever and systemic symptoms is reduced by 1-2 days. 

The third major difficulty in developing cold cures arises from the fact that the HRVs are RNA viruses. When presented with any selective pressure, including chemotherapeutic or antibody challenge, RNA viruses mutate rapidly [9]. This ability to mutate is most clearly illustrated in influenza viruses (RNA viruses), where new strains continuously arise to circumvent immunity in a population. Influenza A viruses have been shown to mutate around the anti-influenza drug Amantadine, after a single passage through a susceptible human host. The mutated viruses shed from a host treated with Amantadine are now resistant to Amantadine. These mutated viruses appear to be as virulent as the parent strain of virus [10]. 

Resistance Influenza A resistance to amantadine and rimantadine is not a clinical problem as yet, although some viral isolates have shown a high incidence of resistance. Resistance has been shown to be due to a change in one amino acid of the M2 matrix protein. Cross-resistance occurs between the two drugs. 

Therapies for typical human influenza viruses should work in treating avian influenza infection in humans however, influenza viruses can become resistant to drugs such as amantadine and rimantadine, decreasing their effectiveness. Currently no vaccine is available to protect humans against the H5N1 virus that causes... 

Stiyjer R, Sti ous RD, Shaked G, Bai F, Feldman B, Kotler M, PolakL, Rosenzcwaig S, Weizman A (2003) Amantadine as augmentation tlierapy in tlie management of ti eatment-resistant depression, hit Clin Psychophaimacol 18 93-96. 

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. 

Heider H, Adamczyk B, Presber HW, Schroeder C, Feldblum R, Indulen MK. Occurrence of amantadine- and rimantadine-resistant influenza A virus strains during the 1980 epidemic. Acta Virol 1981 25(6) 395 00. 

The clinical use of amantadine has been limited by side effects, which may be due to inhibition of endogenous ion channel activity [16] and to the rapid emergence of resistant viral strains [17]. 

Resistance can occur through a number of consequences of viral mutation. There may be reduced phosphorylation of the dmg (for example with nucleoside analogues), alteration of viral enzyme targets (for example with reverse transcriptase inhibitors), or alteration of target channel protein (for example with amantadine). 

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. 

Resistant variants are selected readily by virus passage in the presence of drug and have been recovered from treated persons. Resistance with over 100-fold increases in inhibitory concentrations has been associated with single nucleotide changes leading to amino-acid substitutions in the transmembrane region of M2. Amantadine and rimantadine share aoss-susceptibility and resistance (see Figure 19). 

MECHANISMS OF ACTION AND RESISTANCE Amantadine and rimantadine inhibit an early step in viral replication, probably viral uncoating for some strains, they also have an effect on a late step in viral assembly probably mediated through altering hemagglutinin processing. The primary locus of action is the influenza A virus M2 protein, an integral membrane protein that functions as an ion channel. 

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