The effects of peroral or local aerosol administration of 1-aminoadamantane hydrochloride (amantadine hydrochloride) on influenza infections of the ferret

Fenton, Robert J.; Bessell, Christine J.; Spilling, C. R.; Potter, C. W.

doi:10.1093/jac/3.5.463

Cited by 21 publications

(13 citation statements)

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“…In accord with previous studies of aerosol amantadine therapy in animal models of influenza (7,35,38), aerosol treatments were generally well tolerated. Nasal irritation, rhinorrhea, and disagreeable taste occurred in all subjects receiving treatments with a 2.5-g/100 ml solution concentration, but no adverse effects were observed with the 1.0-g/100 ml concentration.…”

Section: Methodssupporting

confidence: 83%

“…Studies of experimentally induced influenza A virus infections of animnals have found greater therapeutic effects when amantadine was administered by the respiratory route as a smallparticle aerosol, as compared with parenteral (38) or oral (7,35) administration. These advantages of topical therapy were demonstrated with dosages of amantadine lower than those given by the other routes.…”

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confidence: 99%

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Amantadine aerosols in normal volunteers: pharmacology and safety testing

Hayden¹,

Hall²,

Douglas³

et al. 1979

Antimicrob Agents Chemother

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The acceptability and pharmacology of intermittent aerosol administration of amantadine was assessed in healthy volunteers. Amantadine solutions of 2.5, 1.5, or 1.0 g/100 ml were used for 12 30-min, twice-daily aerosol treatments in 15 subjects. Overall, the aerosol treatments were well tolerated. During and up to 1 h after aerosol exposures, nasal irritation, rhinorrhea, dysgeusia, or a combination of symptoms was experienced by some of the subjects receiving either of the two higher amantadine concentrations. Aerosol treatments were associated with small but statistically significant decreases in maximal expiratory flow rates. One hour after aerosol treatments with the 1.0-g/100 ml solution, amantadine levels in nasal wash samples (mean, 30.3 micrograms/ml; range, 1.7 to 108 micrograms/ml) greatly exceeded blood and nasal wash levels reported after oral administration. Amantadine can be administered safely by small-particle aerosol to humans in doses that could be expected to exert an antiviral effect in influenza A virus infections.

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Section: Methodssupporting

confidence: 83%

mentioning

confidence: 99%

Amantadine aerosols in normal volunteers: pharmacology and safety testing

Hayden¹,

Hall²,

Douglas³

et al. 1979

Antimicrob Agents Chemother

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“…The ferret has proved to be a suitable animal model for studying the pathogenicity of influenza virus strains and their susceptibility to antiviral agents [34][35][36]. In the present study, the virulence and the zanamivir susceptibility of variant 229Ile were evaluated in ferrets after inl challenge.…”

Section: Monitoring Of Influenza Virus Susceptibility To the Commercimentioning

confidence: 99%

Characterization of 2 Influenza A(H3N2) Clinical Isolates with Reduced Susceptibility to Neuraminidase Inhibitors Due to Mutations in the Hemagglutinin Gene

et al. 2002

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Previous studies have shown that amino acid changes in the hemagglutinin (HA) gene of influenza viruses may result in decreased susceptibility to neuraminidase inhibitors (NAIs) in vitro. However, the emergence and characteristics of such HA variants in the clinical setting remain poorly studied. Herein, we report 2 influenza A(H3N2) isolates, from untreated patients, harboring an Arg229-->Ile substitution in the HA1 gene. The Ile229 variants were as sensitive as the Arg229 viruses to zanamivir and oseltamivir in neuroaminidase inhibition assays but were significantly less susceptible (by 60-140-fold) in cell-based assays. Although the Ile229 variants adsorbed less efficiently to Madin-Darby canine kidney (MDCK) cells in kinetic binding assays, they remained very sensitive to zanamivir in ferrets. Our study shows the importance of the HA1 229 residue in virus binding to MDCK cells and confirms the unreliability of cell-based assays in predicting the in vivo susceptibility of HA variants to NAIs.

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“…This method of drug administration usually results in higher concentrations of drug at the site of infection than systemic administration does, may decrease or ameliorate systemic toxicities seen after systemic administration, and has been more effective than the systemic administration of antiviral agents in murine (31) and ferret (9) animal models of acute influenza virus infection. SPA delivery of antiviral agents has also been effective in the treatment of human respiratory viral diseases (13,14,17,22,24,28).…”

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confidence: 99%

Safety and pharmacokinetics of rimantadine small-particle aerosol

Atmar

Greenberg

Quarles

et al. 1990

Antimicrob Agents Chemother

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The safety and pharmacokinetics of rimantadine administered by small-particle aerosol were assessed in healthy adults and adults with acute influenza virus infection. Aerosolized rimantadine delivered at a concentration of 40 ,Ig/liter of air was associated with nasal burning and irritation in normal volunteers. A concentration of 20 ,ug/liter of air was well tolerated for up to 12 h by normal volunteers and was not associated with any changes in pulmonary function, as measured by routine spirometry, plethysmography, or diffusion capacity of carbon monoxide. Mean peak levels of drug in serum were approximately 10-fold lower after 12 h of aerosol administration than they were after oral administration of 200 mg (29.7 versus 255 ng/ml, respectively), while mean nasal wash levels were approximately 100-fold higher (6,650 versus 66.6 ng/ml, respectively). Elimination half-lives were similar after both aerosol and oral administration (24.1 and 25.2 h, respectively), and rimantadine urinary excretion was <1% per 24 h in both groups. Twenty micrograms of aerosolized rimantadine per liter of air given 12 h daily for 3 days to nine adults with acute influenza virus infection was well tolerated. Levels in plasma after 12 h of aerosol inhalation were similar to those in normal volunteers, but were higher at the end of the third treatment than they were at the end of the first treatment (88.3 versus 47.9 ng/ml, respectively). Thus, rimantadine delivered via small-particle aerosol at a dose of 20 jig/liter of air was well tolerated in normal volunteers and in those with acute influenza and was associated with high local concentrations.Small-particle aerosol (SPA) delivery of antiviral agents was evaluated for the treatment of viral respiratory tract infections. This method of drug administration usually results in higher concentrations of drug at the site of infection than systemic administration does, may decrease or ameliorate systemic toxicities seen after systemic administration, and has been more effective than the systemic administration of antiviral agents in murine (31) and ferret (9) animal models of acute influenza virus infection. SPA delivery of antiviral agents has also been effective in the treatment of human respiratory viral diseases (13,14,17,22,24,28).Rimantadine has better antiviral activity against some influenza A virus strains than amantadine does (5), is better tolerated when taken orally (8), and is effective as a prophylactic (8, 35) and therapeutic (20,26,30,34,35) agent in influenza A virus infections. Hayden et al. (22) have previously reported the use of rimantadine delivered by ultrasonic nebulizer in subjects given an attenuated influenza A virus; except for minor complaints, the drug was well tolerated. No pharmacokinetic data were reported.Although the combination of amantadine or rimantadine with ribavirin has been shown to have additive or synergistic activity in vitro (6, 21) and when administered systemically in a murine model of acute influenzal pneumonia (11, 33), only the combination o...

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The effects of peroral or local aerosol administration of 1-aminoadamantane hydrochloride (amantadine hydrochloride) on influenza infections of the ferret

Cited by 21 publications

References 0 publications

Amantadine aerosols in normal volunteers: pharmacology and safety testing

Amantadine aerosols in normal volunteers: pharmacology and safety testing

Characterization of 2 Influenza A(H3N2) Clinical Isolates with Reduced Susceptibility to Neuraminidase Inhibitors Due to Mutations in the Hemagglutinin Gene

Safety and pharmacokinetics of rimantadine small-particle aerosol

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