Small-Particle Aerosols of Antiviral Compounds in Treatment of Type A Influenza Pneumonia in Mice

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.

Section: Methodssupporting

confidence: 82%

mentioning

confidence: 99%

Amantadine aerosols in normal volunteers: pharmacology and safety testing

Hayden¹,

Hall²,

Douglas³

et al. 1979

“…treatment when equivalent doses were compared. (5). Although the effect of aerosol treatment differed significantly from that of the same dosage given i.p.…”

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confidence: 89%

“…Recently, ribavirin (1-3-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) was found to be effective for the treatment of type A influenza virus infections in mice (1,(3)(4)(5). These experiments indicated that small-particle aerosols (mass median diameter, 1.4 gm) of ribavirin were more effective in reducing mortality, lesions in the lung, and virus concentrations in the lungs than approximately equivalent doses of drug given intraperitoneally (i.p.)…”

mentioning

confidence: 99%

Response of Influenza Virus-Infected Mice to Selected Doses of Ribavirin Administered Intraperitoneally or by Aerosol

Berendt

Walker

Dominik

et al. 1977

Self Cite

The effects of graded doses of ribavirin administered either by aerosol or intraperitoneally were compared in influenza virus-infected mice. The median effective dose values (based upon percent survival) were 3.3 and 15.8 mg/kg per day for the aerosol and intraperitoneal routes, respectively. Lung lesion scores and titer of virus were lower after aerosol than intraperitoneal therapy.Recently, ribavirin (1-3-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) was found to be effective for the treatment of type A influenza virus infections in mice (1, 3-5). These experiments indicated that small-particle aerosols (mass median diameter, 1.4 gm) of ribavirin were more effective in reducing mortality, lesions in the lung, and virus concentrations in the lungs than approximately equivalent doses of drug given intraperitoneally (i.p.) (4). However, the data did not indicate how much better aerosol administration was than i.p. in terms of dosage required to achieve the same effect, i.e., how much ribavirin was required to achieve an effective dose that would allow >50% of the mice to survive (ED50). This information would be helpful when considering the possible administration of ribavirin by aerosol for the treatment of humans, especially if a significant therapeutic advantage was gained by using the aerosol route.The objective of this research was to determine the response of influenza virus-infected mice to selected doses of ribavirin given either by aerosol or i.p.The procedures employed for housing, infecting, and treating mice [Tac:(SW)fBR] have been described by Stephen et al. (4). Four selected doses of ribavirin were administered by each route. Doses ranged from 2.5 to 20 mg/kg per day by aerosol and from 5.0 to 40.0 mg/kg per day by the i.p. route. Treatment was initiated at 6 h after exposure to the virus and was repeated daily for a total of 5 days. i.p. injections were given once daily at the same time as the aerosols. A virus control group received no treatment. The degree of gross pathology in the lungs (lung lesion score) was evaluated in three mice on day 4 and in five mice on day 7 by 1 Present address: Plum Island Animal Disease Center, P.O. Box 848, Greenport, NY 11944. methods that have been described previously (4). The concentration of virus in the lungs was also determined on day 4 by previously described methods (5). Survival was recorded daily for 21 days in 25 mice that were randomly allocated for this purpose from each treatment group. Survival data from five replicate experiments were analyzed by probit analysis (2), and the dose of ribavirin yielding 50% survival (ED50) was calculated together with 95% confidence limits. Lung lesion scores and lung virus concentration data were evaluated by analysis of variance.The results are shown graphically in Fig. 1. The ED50 values after aerosol and i.p. administration of ribavirin were 3.3 mg/kg per day (95% confidence limits, 2.5 to 4.3) and 15.8 mg/ kg per day (95% confidence limits, 12.7 and 19.5), respectively. The slopes (data not shown) for the regre...

“…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).…”

mentioning

confidence: 99%

Safety and pharmacokinetics of rimantadine small-particle aerosol

Atmar

Greenberg

Quarles

et al. 1990

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...