Biomedical subjects
R J Whitley
Publications and source records attributed to R J Whitley.
Effect of (S)-1-[(3-hydroxy-2-phosphonyl methoxy) propyl] cytosine on the replication and morphogenesis of herpes simplex virus type 1.
Treatment of African green monkey kidney cells with 1 microgram/ml of (S)-1-[(3-hydroxy-2-phosphonyl methoxy) propyl] cytosine (HPMPC) inhibited the release of infectious herpes simplex virus type 1 (HSV-1) by more than 90%. Electron microscopic observations of HPMPC-treated monkey kidney cells demonstrated few intracellular or extracellular viral particles. The viral particles seen were without dense cores. In addition, HPMPC blocked cell fusion induced by HSV-1 in monkey kidney cells. Immunoblot analysis showed that HPMPC significantly blocked the expression of HSV-1-specific proteins. Furthermore, HPMPC inhibited the synthesis of viral DNA as determined by in situ hybridization. These results indicate that HPMPC inhibits the replication of HSV by blocking one of the events involved in DNA synthesis.
Acyclovir treatment of varicella in otherwise healthy adolescents. The Collaborative Acyclovir Varicella Study Group.
STUDY OBJECTIVE: To determine whether orally administered acyclovir is of therapeutic benefit for varicella in otherwise healthy adolescents, and to compare the severity of the disease in adolescents with that in younger children. DESIGN: Multicenter, randomized, placebo-controlled, double-blind trial. SETTING: Patients' homes and university hospital clinics. PATIENTS: Sixty-eight adolescents between 13 and 18 years of age with varicella entered the study. Of the 62 adolescents with laboratory-confirmed varicella who were included in the final analysis, 31 received acyclovir and 31 received placebo. INTERVENTIONS: Placebo or an 800 mg acyclovir tablet was given orally four times daily for 5 days, beginning within 24 hours of onset of rash. MEASUREMENTS AND MAIN RESULTS: Acyclovir recipients had significant reductions in times to cessation of new lesion formation (p less than 0.001), maximum number of lesions (p = 0.019), and defervescence (p = 0.045). Mean constitutional illness score was significantly reduced on day 4 (0.5 vs 1.5, p = 0.05), as was the mean number of residual hypopigmented lesions present on 28-day follow-up examination (22.7 vs 92.7, p = 0.018). Two complications, both bacterial superinfections, occurred in placebo recipients. Adverse experiences and varicella-zoster virus antibody titers measured 28 days after enrollment were similar in both treatment groups. Comparison of placebo recipients with children 2 to 12 years of age participating in a companion study indicated that varicella is more severe in adolescents: mean maximum total lesions (421 vs 347, p = 0.003), mean maximum constitutional illness score (3.1 vs 2.2, p = 0.032), and mean number of residual lesions (92.7 vs 33.2, p = 0.01) were all greater in the adolescent population. CONCLUSIONS: Oral acyclovir therapy is safe and effective for treatment of varicella in otherwise healthy adolescents; this may be an appropriate subgroup for treatment with antiviral drugs because the disease is more severe in them than in younger children.
Prevalence of herpes simplex virus antibodies in dental students.
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Neonatal herpes simplex virus infections: pathogenesis and therapy.
Neonatal herpes simplex virus (HSV) infections are of increasing incidence in North America, now occurring at a rate of approximately one in 3,500 to one in 5,000 deliveries per year. Disease manifests as one of three forms; namely, infection: localized to the skin, eye and mouth (SEM), encephalitis (CNS), or disseminated disease. With the advent of antiviral therapy, it has become possible to decrease mortality and improve morbidity for babies suffering from infection. Advances in antiviral therapy have allowed for prevention of disease progression beyond states of SEM involvement. Furthermore, life threatening infections of the CNS or of multiple organs, have mortality with either acyclovir or vidarabine therapy. Now approximately 15% (CNS) and 50% (disseminated disease) of babies die from neonatal HSV disease. The results of ongoing studies in the United States will summarize the pathogenesis and treatment of neonatal HSV infection.
Distribution of adenine arabinoside and interferon.
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Acyclovir kinetics after intravenous infusion.
The disposition and safety of the antiviral drug acyclovir were studied in 14 subjects with advanced malignancies. Acyclovir was administered by a 1-hr intravenous infusion at doses of 0.5, 1.0, 2.5, and 5.0 mg/kg. At the end of infusion, mean peak plasma levels (+/- SEM), determined by radioimmunoassay, were 6.4 +/- 0.7, 12.1 +/- 2.3, 14.9 +/- 2.7, and 33.7 +/- 7.1 microM. The plasma concentration-time profiles could be described by a biexponential equation. The half-life of acyclovir in the slow disposition phase ranged from 2.2 to 5 hr and the drug was detected in the plasma for at least 18 hr after infusion. The total body clearance ranged from 117 to 396 ml/min/1.73 m2. A proportionality between area under the curve and dose suggests that acyclovir exhibits dose-independent kinetics in the dose range studied. There was wide variation in cumulative urinary excretion of unchanged drug, ranging from 30 to 69% of the dose. From renal clearances of acyclovir, which were higher than creatinine clearances, it appears that both glomerular filtration and tubular secretion contribute to its renal excretion. Analysis of the urine by reverse-phase high-performance liquid chromatography revealed the presence of the metabolite 9-carboxymethoxymethylguanine. There was no indication of toxicity either clinically or from laboratory findings in any of the study subjects. This study demonstrates that in addition to selectivity and low toxicity, the kinetic profile and metabolic disposition of acyclovir make it an attractive candidate for therapy in a variety of herpes infections.
Identification of patients with increased risk of infection with herpes simplex virus after renal transplantation.
Forty-nine recipients of renal allografts were studied for infection with herpes simplex virus (HSV) before and at sequential intervals after transplantation. Forty-four (90%) of the patients studied were initially seropositive for neutralizing antibody to HSV type 1. HSV was not shed prior to transplantation nor by any of the five seronegative recipients after transplantation. Twenty-nine (66%) of the 44 seropositive patients shed virus postoperatively: 23 in saliva, three in urine, and three in both sites. Twenty (63%) of 32 seropositive patients examined developed herpetic mucocutaneous lesions. Both viral shedding and lesions were most prevalent during the first four weeks after transplantation. Twenty-nine (85%) of 34 patients with antibody titers of 1:256-1:4,096 and zero of 10 with titers of 1:8-1:128 shed HSV postoperatively (P less than 0.0001). The group with high antibody titers before transplantation were also more likely to develop lesions after transplantation (P = 0.002) as were those with a positive history (P = 0.017). The ability to predict symptomatic HSV recurrences in renal transplant patients could be a valuable aid in identifying individuals with which to evaluate antiviral compounds.
Outcome of renal transplantation in patients with primary cytomegalovirus infection.
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Effect of primary and recurrent cytomegalovirus infections upon graft and patient survival after renal transplantation.
One hundred sixty-four patients were prospectively studied for evidence of cytomegalovirus (CMV) infection after renal transplantation to determine the effect of primary and recurrent CMV infection on early graft and patient survival. Primary infections occurred in 62% (21 of 34) of pretransplant seronegative recipients and recurrent infection infection in 93% (121 of 130) of seropositive recipients. Symptomatic infections occurred in 81% (17 of 21) of primarily infected and 31% (37 of 121) of recurrently infected recipients. CMV infections (determined by initial virus excretion) occurred in 86% of the primarily infected and 96% of the recurrently infected symptomatic recipients by the 9th post-transplant week. In contrast, only 53% of nonsymptomatic recipients excrete virus by the 9th week. Primarily infected recipients experienced a significantly lower graft survival at 6 months than uninfected seronegative or recurrently infected patients. However, there was no significant difference in patient or graft survival at 1 year. Recipients who developed recurrent symptomatic infections had a significantly lower graft and patient survival than those recipients who developed nonsymptomatic recurrent infections (P less than 0.0002 patient survival and P less than 0.001 graft survival at 12 months).
Serum antibody levels as risk factors in the dissemination of herpes zoster.
Serum antibody levels against varicella-zoster virus (VZV) were examined by immune adherence hemagglutination assay (IAHA), indirect fluorescent antibody (IFA) assay, and complement fixation techniques in 67 immunocompromised patients with localized and disseminated herpes zoster. In the serum obtained initially, undetectable IAHA titers were found in 56.5% of the patients with disseminated zoster compared with 18.2% of those with localized zoster. When serum obtained within the first seven days of illness was analyzed, undetectable IAHA titers and IFA titers of less than 32 were noted in 77.8% of those with disseminated zoster but in only 18.5% of those with localized disease. Peak serum antibody titers in patients with disseminated zoster were eventually equal to or greater than those in localized zoster. The patient groups were comparable in age, underlying disease, and therapy, although Hodgkin's disease was more frequent in patients with disseminated zoster. Thus, the absent IAHA or low IFA levels of circulating antibody early in illness were highly significant risk factors in dissemination of virus in herpes zoster.
Developmental aspects of adenine arabinoside for parenteral therapy of human herpesvirus infections.
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Purification and characterization of proteins excreted by cells infected with herpes simplex virus and their use in diagnosis.
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Productive infection with cytomegalovirus and herpes simplex virus in renal transplant recipients: role of source of kidney.
Forty patients were prospectively studied for infection with cytomegalovirus (CMV) and herpes simplex virus (HSV) after renal transplantation. Although 85% had antibody to CMV and 95% had antibody to HSV prior to transplantation, excretion of CMV was found in 92.5%, usually as viruria, and HSV was recovered from 70%, most often from the oropharynx. Shedding of HSV reached a peak within the first month after transplantation when immunosuppression was most intense and then rapidly declined. In contrast, excretion of CMV was found in a greater proportion of patients during each interval up to about six months after transplantation and subsequently persisted in the majority of patients. Both serologic responses and viral isolation rates indicated more rapid activation of CMV but not of HSV in recipients of kidneys from cadavers than in patients who received kidneys from living related donors. At 60 days after transplantation, 76% of the recipients of kidneys from cadavers and only 33% of the recipients of kidneys from living, related donors had shed CMV (P = 0.003). These differences could not be accounted for by immunosuppressive treatment. Excretion of HSV was clearly associated with the time of most intense immunosuppression, but the major factor in initiation and maintenance of productive infection with CMV appeared to be the host vs. graft reaction.
Current status of antiviral chemotherapy.
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Herpes simplex virus encephalitis: an atypical presentation.
Herpes simplex virus (HSV) encephalitis is an acute febrile encephalopathy usually characterized by disordered mentation, fever, headache, and focal seizures. We have described a patient with HSV encephalitis whose initial illness was manifested solely as a seizure disorder. Consequently, the diagnosis was not made until late in the hospital course. This atypical presentation of HSV encephalitis is emphasized to facilitate recognition of this disorder and to prompt early diagnostic brain biopsy so that appropriate antiviral therapy can be instituted.
Developmental aspects of selected antiviral chemotherapeutic agents.
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