Sensitivity of Clinical Isolates of Human Cytomegalovirus to 9-(1,3-Dihydroxy-2-Prop.oxymethyl)Guanine

Cytomegalovirus (CMV) often persists in the lungs of marrow transplant patients with CMV pneumonia, despite ganciclovir (GCV) treatment. To determine whether GCV resistance contributes to viral persistence, the susceptibilities of CMV isolates from diagnostic bronchoalveolar lavage samples and CMV isolates obtained during treatment or from autopsy lung tissue from 12 patients were compared by DNA hybridization. Resistance (50% effective dose, > 12 ,uM) was detected in an isolate from only one patient who had also received several courses of GCV. GCV resistance did not explain the persistence of CMV in the lung.Although the combination of ganciclovir (GCV) and intravenous immunoglobulin (i.v.-Ig) has decreased the rate of mortality from cytomegalovirus (CMV) pneumonia in marrow transplant recipients, mortality remains high at 30 to 50% (3, 20), and as many as 10% of treated patients have relapses (2). CMV was still detected in 80% of patients with CMV pneumonia at our institution in a routine follow-up bronchoalveolar lavage (BAL) specimens after 9 days of treatment (22), without a reduction in viral titer (23). These findings raised the question of whether resistance to GCV could explain the persistence of CMV in the lungs of some patients, despite treatment.All 12 patients examined in the present study were allogeneic bone marrow transplant recipients with CMV pneumonia. CMV pneumonia was defined as described previously (23) and was treated with GCV, 5 mg/kg of body weight twice daily for 2 weeks, and i.v.-Ig (Cutter Biological, Miles Laboratories Inc., Berkeley, Calif.), 500 mg/kg on alternate days for 2 weeks. GCV was continued at 5 mg/kg daily for up to 30 days. Relapse was defined as the recurrence of symptoms, worsening pulmonary infiltrates on chest radiograph (20), and detection of CMV in BAL specimens after the completion of a course of treatment for the initial episode. Only two patients had received GCV prior to the episode of CMV pneumonia being studied. With the exception of one patient, all patients had received acyclovir (ACV) intravenously as CMV prophylaxis; ACV was given at 500 mg/M2 every 8 h from the day of pretransplant conditioning to the day of discharge from the hospital (17).CMV isolates were obtained from the initial diagnostic BAL specimens, from follow-up BAL specimens 9 days after starting GCV and i.v.-Ig, when routine follow-up BAL was being performed to assess the subsequent duration of GCV therapy, or from autopsy lung tissue after 7 to 32 days of treatment. Samples from urine, throat, and blood were obtained weekly for culture of CMV. All For susceptibility testing, isolates from patients and isolates 8708 and 8704 were first thawed and were then reinoculated into tube cultures of human foreskin fibroblasts and passaged one to four times until the cytopathic effect had progressed to 75 to 100% of the monolayer. CMV-infected cells were then removed with 0.05% trypsin and were resuspended in Dulbecco's modification of Eagle's medium with 10% fetal bovine serum (DME-10). Fifty mil...

supporting

confidence: 87%

Ganciclovir sensitivity of cytomegalovirus at diagnosis and during treatment of cytomegalovirus pneumonia in marrow transplant recipients

Slavin

Bindra

Gleaves

et al. 1993

“…Few antiviral agents have shown efficacy against CMV infections, and there is a clear need for new potent agents that can be used for the prevention and treatment of CMV infections. The antiviral compound 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) is the most potent agent against CMV described to date (5,7,16,18). However, its usefulness remains limited to specific sites of CMV infections, such as the eye and gastrointestinal tract (5,6,14,19).…”

mentioning

confidence: 99%

Efficacy of S26308 against guinea pig cytomegalovirus infection

Chen

Griffith

Lucia

et al. 1988

Prophylactic use of antiviral agents against cytomegalovirus (CMV) is particularly indicated for the immunocompromised host because morbidity and mortality due to CMV occur most frequently following immunosuppression. We have evaluated the new Riker compound S26308 for its therapeutic and prophylactic antiviral activity against CMV in guinea pigs. The efficacy of the compound was assessed in vitro in guinea pig embryo cells and in vivo in both immunocompetent and immunocompromised guinea pigs. Guinea pig CMV plaque formation was reduced only in cells treated with S26308 prior to virus infection. The antiviral activity remained even when the compound was removed after virus absorption and was due to neither virus destruction nor inhibition of cell growth. The frequency of viremia was reduced in guinea pigs for which S26308 therapy was initiated 24 h prior to virus inoculation compared with sham-treated animals. This reduction in the frequency of viremia did not prevent virus spread to target tissues but did result in a reduction of the severity of CMV-induced disease in immunocompromised guinea pigs. Low levels of interferon were detected in supernatants of S26308-treated cells, and interferon was detected in the serum of guinea pigs given S26308. These results indicate that S26308 can induce interferon and reduce CMV infectivity in vivo and in vitro when used prophylactically. This antiviral activity, although modest, was accompanied by beneficial effects on CMV-induced morbidity and mortality. Prophylactic use of S26308 in combination with other therapeutic agents may be a useful strategy against CMV infections.A broad spectrum of morbidity and mortality is associated with infections of humans with cytomegalovirus (CMV). Few antiviral agents have shown efficacy against CMV infections, and there is a clear need for new potent agents that can be used for the prevention and treatment of CMV infections. The antiviral compound 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) is the most potent agent against CMV described to date (5,7,16,18). However, its usefulness remains limited to specific sites of CMV infections, such as the eye and gastrointestinal tract (5,6,14,19). In addition, mutants of human CMV resistant to DHPG have been isolated (2), and development of CMV retinitis in a patient treated with DHPG for CMV colitis has been reported (17). Evaluation of the efficacy of candidate antiviral compounds requires not only testing in vitro, but also in vivo studies in a well-defined experimental model. The guinea pig model of CMV infection is well suited for testing candidate antiviral compounds because the pathogenesis of the viral infection in this animal model closely approximates that in the human host (1).The new Riker drug S26308, 1-isobutyl-lH-imidazo(4,5-c)quinolin-4-amine (Fig. 1), has shown efficacy against herpes simplex virus infections in an experimental model (C. J.

“…A newer agent, 9-(1-3-dihydroxy-2-propoxymethyl)guanine (DHPG), has been shown to be effective in vitro (6,7,9) and has had limited effectiveness in treating HCMV infections (3,8). In addition, alpha interferon and anti-HCMV immunoglobulin have been shown to have some effectiveness when administered prophylactically (4,16).…”

mentioning

confidence: 99%

9-(1-3-Dihydroxy-2-propoxymethyl)guanine prevents death but not immunity in murine cytomegalovirus-infected normal and immunosuppressed BALB/c mice

Wilson

Medearis

Hansen

et al. 1987

Immunosuppressed (from treatment with cortisone acetate and anti-thymocyte globulin) and control adult female BALB/c mice, latently infected with murine cytomegalovirus (MCMV) or lethally challenged (106 PFU) with MCMV intraperitoneally, were treated with 9-(1-3-dihydroxy-2-propoxymethyl)guanine (DHPG) A newer agent, 9-(1-3-dihydroxy-2-propoxymethyl)guanine (DHPG), has been shown to be effective in vitro (6, 7, 9) and has had limited effectiveness in treating HCMV infections (3,8). In addition, alpha interferon and anti-HCMV immunoglobulin have been shown to have some effectiveness when administered prophylactically (4, 16).The murine CMV (MCMV) system provides a useful model for exploring the potential utility of these approaches. Shanley et al. (14)