Inhibitors Of Herpes Simplex Virus And Human Cytomegalovirus

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The eight human herpes viruses cause a variety of pathophysiological conditions ranging in severity from mild cold sores to life threatening illnesses in immunocompromised patients. While herpes simplex virus (HSV) types 1 and 2 typically cause localized cold sores and genital herpes, other members of the herpesviridae family can be more problematic. Varicella zoster virus (VZV) is the causative agent in chicken pox whilst human cytomegalovirus (HCMV) is particularly difficult for the immunocompromised population, including AIDS patients where clinical manifestations include retinitis, colitis, oesophagitis, and pneumonia (78). Epstein-Barr virus (EBV) is responsible for mononucleosis in immunocompetent patients and lymphoma in immunocompromised individuals. Finally, HHV-6, HHV-7 and HHV-8 are the remaining known pathogenic herpes viruses of which HHV-8 is responsible for the debilitating effects of Kaposi's sarcoma. Nine antiviral agents are licensed to treat infections caused by the herpes virus family, all but one of which, fomiversen, terminate viral DNA synthesis by inhibiting the viral DNA polymerase (80,81). Resistance to current antiherpetics is modulated primarily by the thymidine kinase (TK), the UL97 phosphotransferase in HCMV and the DNA polymerase (82-86).

Valacyclovir hydrochloride (Valtrex™) 31 was approved in September 2002 for the treatment of cold sores in healthy adults and acyclovir (Zovirax™) 32 cream was approved for the treatment of recurrent herpes labialis or cold sores (87). Valomaciclovir stearate (MIV-606, 33) has shown promise in P2 clinical trials for the treatment of herpes zoster with P3 trials planned (88). Maribavir (1263W94, 34), an inhibitor of the HCMV UL97 protein kinase (ICso = 3 nM), has been dropped from P2 clinical development for the treatment of HCMV infection (89-91). Data from a P1 clinical trial in HIV-1 infected men with asymptomatic HCMV shedding has been released (92,93). Maribavir demonstrated in vivo anti-HCMV activity in all of the dosage regimens tested (100, 200, and 400 mg tid, and 600 mg bid), with mean reductions in semen HCMV titers of 2.9 to 3.7 logio PFU/mL (92).

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