Use of Cotton Rats to Evaluate the Efficacy of Antivirals in Treatment of Measles Virus Infections

Wyde, Philip R.; Moore-Poveda, Donna K.; Clercq, Erik De; Neyts, Johan; Matsuda, Akira; Minakawa, Noriaki; Guzman, Efrain; Gilbert, Brian E.

doi:10.1128/aac.44.5.1146-1152.2000

Cited by 28 publications

(13 citation statements)

References 37 publications

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“…or s.c. administration is consistent with studies in cotton rats where either RBV aerosol or RBV i.p. was shown to maximally reduce pulmonary RSV titers by 1.2-2.3 log units (Wyde et al 2000) and in infants where aerosolized RBV reduced RSV titers in nasal wash isolates by 1-2.5 log units (Hall et al 1983;Englund et al 1994). Furthermore, RBV's antiviral activity following oral administration is consistent with its systemic bioavailability.…”

Section: Discussionmentioning

confidence: 83%

Primary infection of mice with high titer inoculum respiratory syncytial virus: characterization and response to antiviral therapy

Bolger¹,

Lapeyre²,

Dansereau³

et al. 2005

Can. J. Physiol. Pharmacol.

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Intranasal infection of BALB/c mice with respiratory syncytial virus (RSV)-A2 (0.5 x 10(8) - 2.0 x 10(8) plaque-forming units, PFU) produced disease characterized by weight loss (2-3 g) and mortality (60%-100%) with the mean day of death ranging from 6-7 d after infection. The extent of RSV disease was inoculum titer-dependent and required a replication competent virus. Lung titers of virus peaked at 0.5-1 x 10(6) PFU/g wet weight. Bronchoalveolar lavage fluid (BALF) levels of IL-1beta, TNF-alpha, INF-gamma IL-12, IL-6, MIP-1alpha, RANTES, and protein were elevated, whereas IL-2, IL-4, IL-5, IL-13, and IL-10 were unchanged. Histological assessment of lungs revealed marked inflammatory pathology characterized by bronchiolitis, vasculitis, and interstitial pneumonia. Whole-body plethysmography revealed significant disease-associated deficits of respiratory function. Therapy with ribavirin administered either by the intranasal, subcutaneous, or oral route significantly reduced disease in a dose-dependent manner. Delaying the initiation of therapy resulted in a loss of activity for ribavirin. Synagis administered either intramuscularly as a single dose in prophylaxis or intranasally in prophylaxis, followed by therapy, also significantly reduced disease in a dose-dependent manner. Infection of mice with a high titer inoculum of RSV-A2 resulted in severe and fatal pulmonary disease that was responsive to treatment. This model may be useful to characterize the in vivo activity of experimental therapies for RSV infection.

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Section: Discussionmentioning

confidence: 83%

Primary infection of mice with high titer inoculum respiratory syncytial virus: characterization and response to antiviral therapy

Bolger¹,

Lapeyre²,

Dansereau³

et al. 2005

Can. J. Physiol. Pharmacol.

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“…Single-dose prophylactic efficacy in animal models was reported for a number of antiviral agents. These include the RSV inhibitor RFI-641, administered intranasally in cotton rats (18), and the viral attachment inhibitor PAMPS, administered intranasally against both RSV and measles virus in cotton rats (39). Furthermore, the nucleoside analogs cidofovir (31) and acyclovir (30) were effective against cowpox virus and herpes simplex virus, respectively, in mouse models of infection using a single-dose regimen.…”

Section: Discussionmentioning

confidence: 99%

Oral Efficacy of a Respiratory Syncytial Virus Inhibitor in Rodent Models of Infection

Cianci

Genovesi

Lamb

et al. 2004

Antimicrob Agents Chemother

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). In this report, the in vivo efficacy of BMS-433771 against RSV was further examined in the BALB/c mouse and cotton rat host models of infection. By using the Long strain of RSV, prophylactic efficacy via oral dosing was observed in both animal models. A single oral dose, administered 1 h prior to intranasal RSV inoculation, was as effective against infection as a 4-day b.i.d. dosing regimen in which the first oral dose was given 1 h prior to virus inoculation. Results of dose titration experiments suggested that RSV infection was more sensitive to inhibition by BMS-433771 treatment in the BALB/c mouse host than in the cotton rat. This was reflected by the pharmacokinetic and pharmacodynamic analysis of the efficacy data, where the area under the concentration-time curve required to achieve 50% of the maximum response was ϳ7.5-fold less for mice than for cotton rats. Inhibition of RSV by BMS-433771 in the mouse is the result of F1-mediated inhibition, as shown by the fact that a virus selected for resistance to BMS-433771 in vitro and containing a single amino acid change in the F1 region was also refractory to treatment in the mouse host. BMS-433771 efficacy against RSV infection was also demonstrated for mice that were chemically immunosuppressed by cyclophosphamide treatment, indicating that compound inhibition of the virus did not require an active host immune response.

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“…Ribavirin is a broad-spectrum nucleoside analogue with activity against paramyxoviruses, such as human respiratory syncytial virus (hRSV), pneumonia virus of mice, and measles virus, when evaluated with different animal models (10,20). It has also recently been reported to exhibit similar antiviral activities against hRSV and hMPV when evaluated in vitro with LLC-MK2 cells (18).…”

mentioning

confidence: 99%

Effect of Ribavirin and Glucocorticoid Treatment in a Mouse Model of Human Metapneumovirus Infection

Hamelin

Prince²,

Boivin

2006

Antimicrob Agents Chemother

104

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Human metapneumovirus (hMPV)-infected BALB/c mice were treated with ribavirin (40 mg/kg of body weight twice a day intraperitoneally), corticosterone (0.2 mg/ml in water), or both modalities. Ribavirin significantly decreased both hMPV replication in lungs (by 5 log 10 ) and global pulmonary inflammation on day 5 postinfection, whereas glucocorticoids reduced only alveolar and interstitial inflammation, compared to controls.Human metapneumovirus (hMPV) is a newly described member of the Paramyxoviridae family associated with acute respiratory tract infections in all age groups, with more-severe diseases occurring in young children, elderly individuals, and immunocompromised hosts (3,7,8,15). Experimental animal models of hMPV infection have been reported for primates and rodents (9,12,17,19). Notably, the BALB/c mouse has been described as a good and convenient animal model for this virus due to efficient viral replication and significant lung inflammation associated with systemic and respiratory symptoms when a high intranasal inoculum is used (1, 9). Although ribavirin has been reported to decrease hMPV titers in vitro (18), this drug has not been evaluated with animal models. In this study, we assessed the effects of ribavirin with or without glucocorticoids on hMPV replication and pulmonary inflammation by using a previously described BALB/c mouse model (9).Animal studies. Forty-eight 4-to 6-week-old BALB/c mice (Charles Rivers Laboratories, Wilmington, MA) were randomized into six groups of eight mice each, based on weight. On day 0, four groups (32 mice) were infected intranasally with 1 ϫ 10 8 50% tissue culture infective doses (TCID 50 ) of hMPV strain C-85473 (type A) at passage 7 in 25 l of hMPV infection medium as previously reported (9). The other two groups (16 mice) were sham infected with infection medium, and all animals were housed in groups of four in microisolator cages. Groups of hMPV-infected mice were treated with phosphatebuffered saline (PBS), ribavirin (MP Biomedicals, Aurora, OH) at 40 mg/kg of body weight every 12 h, corticosterone (Sigma, St. Louis, MO) at 0.2 mg/ml, or ribavirin and corticosterone. Groups of sham-infected mice were treated with either PBS or ribavirin as described above. Ribavirin and PBS were given intraperitoneally from day 0 to day 5 postinfection, beginning 12 h postinfection, whereas corticosterone was given in water ad libitum from day 3 to day 5. Mice were weighted every day and then sacrificed on day 5 postinfection. The right lungs were homogenized in infection medium and used to determine viral titers in LLC-MK2 cells, whereas the left lungs were used for determination of histopathological scores based on a scale previously described (9,14).

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Use of Cotton Rats to Evaluate the Efficacy of Antivirals in Treatment of Measles Virus Infections

Cited by 28 publications

References 37 publications

Primary infection of mice with high titer inoculum respiratory syncytial virus: characterization and response to antiviral therapy

Primary infection of mice with high titer inoculum respiratory syncytial virus: characterization and response to antiviral therapy

Oral Efficacy of a Respiratory Syncytial Virus Inhibitor in Rodent Models of Infection

Effect of Ribavirin and Glucocorticoid Treatment in a Mouse Model of Human Metapneumovirus Infection

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