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Antimicrobial Agents and Chemotherapy, January 2004, p. 267-274, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.267-274.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Interferon Inducer Ampligen [Poly(I)-Poly(C12U)] Markedly Protects Mice against Coxsackie B3 Virus-Induced Myocarditis

Elizaveta Padalko,1 Dieter Nuyens,2 Armando De Palma,1 Erik Verbeken,3 Joeri L. Aerts,4 Erik De Clercq,1 Peter Carmeliet,2 and Johan Neyts1*

Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy,1 Centre for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, Katholieke Universiteit Leuven, B-3000 Leuven,2 Division of Histopathology,3 Experimental Laboratory Medicine, University Hospitals, Leuven, Belgium4

Received 26 February 2003/ Returned for modification 13 June 2003/ Accepted 2 September 2003

Viral replication, as well as an immunopathological component, is assumed to be involved in coxsackie B virus-induced myocarditis. We evaluated the efficacy of the interferon inducer Ampligen on coxsackie B3 virus-induced myocarditis in C3H/HeNHsd mice. The efficacy of Ampligen was compared with that of the interferon inducer poly(inosinic acid)-poly(cytidylic acid) [poly(IC)], alpha interferon 2b (INTRON A), and pegylated alpha interferon 2b (PEG-INTRON-{alpha}-2b). Ampligen at 20 mg/kg of body weight/day was able to reduce the severity of virus-induced myocarditis, as assessed by morphometric analysis, by 98% (P = 3.0 x 10-8). When poly(IC) was administered at 15 mg/kg/day, it reduced the severity of virus-induced myocarditis by 93% (P = 5.6 x 10-5). Alpha interferon 2b (1 x 105 U/day) and pegylated alpha interferon 2b (5 x 105 U/day) were less effective and reduced the severity of virus-induced myocarditis by 66% (P = 0.0009) and 78% (P = 0.0002), respectively. The observed efficacies of Ampligen and poly(IC) were corroborated by the observation that the drugs also markedly reduced the virus titers in the heart, as detected by (i) quantitative real-time reverse transcription-PCR and (ii) titration for infectious virus content. Whereas the electrocardiograms for untreated mice with myocarditis were severely disturbed, the electrocardiographic parameters were normalized in Ampligen- and poly(IC)-treated mice. Even when start of treatment with Ampligen was delayed until day 2 postinfection, a time at which lesions had already appeared in untreated control animals, a marked protective effect on the development of viral myocarditis (as assessed at day 6 postinfection) was still noted.

* Corresponding author. Mailing address: Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Phone: (32)-16-337353. Fax: (32)-16-337340. E-mail: Johan.Neyts{at}rega.kuleuven.ac.be.

Antimicrobial Agents and Chemotherapy, January 2004, p. 267-274, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.267-274.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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