guanosine-triphosphate and Cytomegalovirus-Infections

Two antiviral compounds, (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine [HPMPC] and 9-(1,3-dihydroxy-2-propoxymethyl)guanine [DHPG], were evaluated for their inhibitory effects on human cytomegalovirus (HCMV) replication in human embryonal fibroblasts and on rat cytomegalovirus (RCMV) replication in rat embryonal fibroblasts. The concentrations of HPMPC or DHPG required to inhibit HCMV plaque formation by 50% were 0.1 and 0.6 micrograms/ml, respectively. For RCMV, these values were 1.1 and 25 micrograms/ml, respectively. For HCMV, the selectivity indices of HPMPC and DHPG, as determined by the ratio of the 50% inhibitory concentration for cell growth to the 50% inhibitory concentration for virus plaque formation, were 1,250 and 140, respectively, and for RCMV, they were 500 and 76, respectively. HPMPC was far more active than DHPG against RCMV infection in vivo as measured by mortality, histopathological changes, and virus titers in organs of immunocompromised RCMV-infected rats. The minimal effective dosage required to prevent mortality from RCMV infection was a single dose of HPMPC at 2 mg/kg of body weight compared with DHPG therapy twice daily at 20 mg/kg/day for 5 days. Furthermore, HPMPC was more effective than DHPG in reducing virus titers in internal organs (P less than 0.01) and in RCMV-induced histopathologic lesions. In contrast to DHPG, which did not show activity when administered 1 day before infection, HPMPC was effective even when administered 7 days before RCMV infection.

Topics: Animals; Antiviral Agents; Cell Survival; Cells, Cultured; Cidofovir; Cytomegalovirus; Cytomegalovirus Infections; Cytosine; Guanosine Triphosphate; Humans; Male; Organophosphonates; Organophosphorus Compounds; Rats; Viral Plaque Assay; Virus Replication

Two novel antiviral pharmacologic strategies were used for therapy of life- and sight-threatening cytomegalovirus (CMV) infection; these were continuous drug infusion by portable pump and individualized patient regimen. 9-(1,3-Dihydroxy-2-propoxymethyl)-guanine (DHPG), an active and recently licensed antiviral drug against cytomegalovirus infection, was administered to five immunocompromised patients with chorioretinitis (all patients), colitis (two), and pneumonitis (three). Through dosage escalation, correlations between plasma levels, toxicity (i.e., myelosuppression), and clinical benefit were ascertained for therapy of acute disease (pneumonitis) as well as long-term therapy (chorioretinitis). Resolution of viremia, pneumonitis, colitis, and chorioretinitis was accomplished with steady-state plasma levels of DHPG approximating the mean ID50 of CMV isolates. The most notable clinical benefit was survival from CMV pneumonia and stabilization of vision. Although no adverse toxicity occurred during the DHPG continuous long-term therapy, survival was limited by the underlying disease.

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Cytomegalovirus Infections; Female; Guanosine Triphosphate; Humans; Infusion Pumps; Retinitis

Nine patients with acquired immunodeficiency syndrome (AIDS) and cytomegalovirus (CMV) retinitis on maintenance therapy with ganciclovir: 9(1,3-dihydroxy-2-propoxymethyl) guanine (DHPG) at high dose (30 mg/kg/week) or low dose (20 mg/kg/week) were tested every 1-2 weeks for CMV isolation from blood, saliva, and urine. Duration of therapy ranged from 1.5 to 12 months (average 5.3 months). During pretreatment and low-dose and high-dose maintenance therapy, CMV was isolated from 48/59 (81%), 90/211 (43%), and 40/290 (14%) of specimens, respectively. Three patients with progressive retinitis had viraemia more frequently than did six patients with stable retinitis, CMV being isolated from 29/47 (62%) and 17/121 (14%) of blood samples, respectively.

Topics: Acquired Immunodeficiency Syndrome; Adult; Cytomegalovirus; Cytomegalovirus Infections; Guanosine Triphosphate; Humans; Male; Middle Aged; Prevalence; Retinitis; Viremia