Inhibition of coxsackie B3 virus induced myocarditis in mice by 2‐(3,4‐dichlorophenoxy)‐5‐nitrobenzonitrile

Abstract

Myocarditis is a common cause of dilated cardiomyopathy, one of the most important single causes of heart transplantation. Coxsackie B viruses (CBV) are considered to be the principal etiological agents of viral myocarditis and direct virus-induced damage to the heart tissue has been suggested to be the main mechanism underlying myocarditis in the murine model [Horwitz et al. 2000 Nat Med 6:693–697]. We demonstrate that 2-(3,4-dichloro-phenoxy)-5-nitrobenzonitrile (DNB), a compound that was earlier shown to exhibit broad-spectrum anti-picornavirus activity is also markedly active against CBV replication in primary human myocard fibroblast. To challenge the hypothesis of [Horwitz et al. 2000 Nat Med 6:693–697] we assessed whether DNB is able to prevent the development of CBV-induced myocarditis in a murine model. Subcutaneous (s.c.) administration of DNB at 250 mg/kg/day, at multiple injection sites (m.i.s.), for a period of seven consecutive days (starting at 1 day before infection) to 4-week old C3H-mice resulted in a (i) 62% reduction in the number of myocarditis foci as compared to the untreated control animals (p = 1.7 × 10⁻¹⁰) and (ii) a concomitant reduction in viral titers in the heart. These findings indicate that selective inhibition of the replication of CBV may have a beneficial effect on the development of viral myocarditis and confirms that direct viral induced damage is the main mechanism underlying CBV-induced myocarditis. Early diagnosis of virus-induced myocarditis will likely be mandatory for an antiviral drug treatment regimen to achieve its greatest clinical benefit. J. Med. Virol. 72:263–267, 2004.