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Biomedical subjects

R J Whitley

Publications and source records attributed to R J Whitley.

At least 55 records · Page 3Linked to original sources
PubMed1998

Treatment of intracranial gliomas in immunocompetent mice using herpes simplex viruses that express murine interleukins.

This report describes a test of the hypothesis that the oncolytic effect of genetically engineered, replication competent herpes simplex viruses (HSV) depends both on cell destruction by the virus and an immune response to the tumor cells induced in an immunocompetent animal system. The oncolytic vector was a HSV recombinant virus in which both copies of the gamma 1 34.5 gene were replaced with the murine genes encoding the cytokine interleukin-4 (IL-4) or interleukin-10 (IL-10). The hypothesis predicted that if an immune response plays a role in survival following intratumoral treatment of tumor-bearing animals with HSV, expression of IL-4 should prolong survival whereas expression of IL-10 should reduce it. The results are that (1) these cytokines can be expressed by HSV in productively infected cells both in vitro and in vivo; (2) HSV-expressing IL-4 or IL-10 genes were able to infect and destroy glioma cells in vitro; (3) intracerebral inoculation of HSV expressing either IL-4 or IL-10 into syngeneic murine glioma GL-261 cells implanted in the brains of immunocompetent C57BL/6 mice produced dramatically opposite physiologic responses. The IL-4 HSV significantly prolonged survival of tumor bearers, whereas tumor-bearing mice that received the IL-10 HSV had a median survival that was identical to that of saline treated controls; (4) immunohistochemical analyses of mouse brains at 3 and 7 days after virus inoculation showed marked accumulation of inflammatory cells composed primarily of macrophages/microglia, with various proportions of CD8+ and CD4+ T cells, but few B lymphocytes. We conclude that the cytokines expressed from genes encoded in the viral genome influence HSV therapy of tumors and this is probably due to the host immune response. Thus, cytokine expression may be an important adjunct to tumor therapy utilizing genetically engineered HSV.

Animals↗
PubMed1998

The identification of risk factors associated with persistent pain following herpes zoster.

Demographic and clinical characteristics of patients with herpes zoster at the time of presentation predict the duration and severity of pain on long-term follow-up. Analyses by Cox's proportional hazard models of six databases from controlled trials of antiviral drugs (total subjects = 2367) identified covariates for zoster-associated pain; all tests for significance were two-sided. Age strongly influenced pain outcome: patients > or = 50 years old were significantly more likely to have prolonged zoster-associated pain compared with those < 30 years old. Patients with prodromal symptoms or moderate or severe pain at presentation were also more likely to experience prolonged zoster-associated pain. Neither time to initiating treatment after rash onset nor sex of patient influenced pain outcome. Advancing age, prodromal symptoms, and acute pain severity at presentation predicted those individuals most at risk of prolonged pain and postherpetic neuralgia. When two or more of these factors were present, the risk of persistent pain was increased.

Adult↗
PubMed1998

Sorivudine versus acyclovir for treatment of dermatomal herpes zoster in human immunodeficiency virus-infected patients: results from a randomized, controlled clinical trial. Collaborative Antiviral Study Group/AIDS Clinical Trials Group, Herpes Zoster Study Group.

The present randomized, double-blind, placebo-controlled, multicenter clinical trial was designed to compare the efficacy and tolerability of sorivudine [1-beta-D-arabinofuranosyl-E-(2-bromovinyl)uracil] and acyclovir for the treatment of dermatomal herpes zoster in human immunodeficiency virus (HIV)-seropositive patients. A total of 170 HIV-seropositive adults presenting with herpes zoster (confirmed by direct fluorescent-antigen testing and/or viral culture) were enrolled and randomized to receive a 10-day course of orally administered sorivudine (40 mg once daily plus acyclovir placebos) or acyclovir (800 mg five times daily plus sorivudine placebo). Patients were monitored daily to document the events of cutaneous healing, pain, zoster-related complications, and drug-related adverse events. Patients were reassessed on days 21 and 28 and then once monthly for 1 year. The primary efficacy endpoint was time to the cessation of new vesicle formation. Secondary efficacy endpoints included times to other events of cutaneous healing, resolution of pain, and frequency of dissemination and zoster recurrence. In a multivariate analysis, sorivudine was superior to acyclovir for reducing the times to the cessation of new vesicle formation (relative risk [RR] = 1.54, 95% confidence interval [CI] = 1.00 to 2.36; P = 0.049) and total lesion crusting (RR = 1.48, 95% CI = 1.07 to 2.04; P = 0.017). In a univariate analysis, there was a trend favoring sorivudine for the cessation of new vesicle formation (median of 3 versus 4 days; P = 0.07) and a significant advantage for time to total lesion crusting (median of 7 versus 8 days; P = 0.02). The time to the resolution of zoster-associated pain, the frequency of dissemination, and the frequency of zoster recurrence were not different between the two treatment groups. Both drugs were well tolerated. Sorivudine is an effective drug for the treatment of herpes zoster in HIV-infected patients and results in accelerated cutaneous healing when compared with acyclovir therapy.

AIDS-Related Opportunistic Infections↗
PubMed1998

Application of competitive PCR to cerebrospinal fluid samples from patients with herpes simplex encephalitis.

The purpose of the present study was to determine if the quantity of herpes simplex virus (HSV) DNA in the cerebrospinal fluid (CSF) of patients with herpes encephalitis would be useful in establishing the prognosis of the disease and to determine the effect of antiviral therapy on the clearance of viral DNA from the CSF. Quantitation of HSV DNA was done by constructing an internal standard (IS) from the glycoprotein B amplicon which had a 25-bp deletion between primer annealing sites. Each CSF specimen was coamplified with the IS and the ratio of the amount of HSV/amount of IS was compared to the ratios on a standard curve constructed with the same IS plus known amounts of HSV DNA. CSF specimens were available from 16 patients who were treated with intravenous acyclovir, and the amount of HSV DNA ranged from < 25 to 18,000 copies per microliter in CSF obtained before or within 4 days of the initiation of acyclovir therapy. Patients with > 100 copies of HSV DNA per microliter were older, were found by computed tomography to have lesions, and had poorer outcomes than patients with < 100 copies. Follow-up CSF specimens were available from seven patients. In six of these seven patients, the HSV DNA levels decreased during therapy. One patient had a twofold increase in HSV DNA levels after 1 week of therapy and died on day 8. The application of this assay may be helpful in establishing the prognosis and in the monitoring of patients with herpes simplex encephalitis.

Acyclovir↗
PubMed1998

Human herpesvirus-6: neurologic implications of a newly-described viral pathogen.

Discovered only 12 years ago, human herpesvirus-6 (HHV-6) has been associated with central nervous system (CNS) findings such as febrile seizures, encephalitis, meningitis, and possibly multiple sclerosis. These manifestations have been reported in both immunocompetent and immunocompromised individuals. The applications of such sophisticated laboratory tools as polymerase chain reaction, in situ hybridization, immunohistochemical staining, and representational difference analysis have expanded knowledge of the spectrum of CNS disease attributable to HHV-6 while delineating pathogenic mechanisms of both primary HHV-6 infection and reactivation from latency. This article reviews existing knowledge of the CNS manifestations of HHV-6, focusing on both clinical aspects of HHV-6 infection and its pathogenesis on neurologic diseases.

Adult↗
PubMed1997

Evaluation of genetically engineered herpes simplex viruses as oncolytic agents for human malignant brain tumors.

Earlier studies have shown that genetically engineered herpes simplex viruses (e.g., HSV-1) are effective in killing malignant tumor cells both in vitro and in various murine tumor models. This report focuses on a panel of five genetically engineered viral mutants of the gamma(1)34.5 gene, which was shown previously to cause reduction in viral replication and associated neurovirulence of HSV. These include R3616, which has both copies of gamma(1)34.5 deleted, R4009, which has a stop codon inserted after codon 28 in both copies of the gamma(1)34.5 gene, R849, which contains a lacZ gene inserted in place of the gamma(1)34.5, R908, which lacks 41 codons in frame after codon 72 of the gamma(1)34.5, and R939, which carries a stop codon precluding the translation of the COOH-terminal domain of the gamma(1)34.5 gene. We report the following: (a) all five mutant HSVs were avirulent in experimental animals but were cytotoxic for human tumor cells in vitro and in vivo; (b) the gamma(1)34.5- HSV replicated in human glioma cells almost as efficiently as wild-type HSV-1(F) based on replication assays, in situ hybridization for viral DNA, and expression of infected cell protein 27; (c) capacity of mutant HSVs to kill human cells derived from glioblastoma multiforme (CH-235MG, D-37MG, D-54MG, D-65MG, U-251MG, U-373MG, and SK-MG-1), anaplastic astrocytoma (Hs-683), anaplastic glioma (U-87MG and U-138MG), gliosarcoma (D-32GS), or normal human astrocytes demonstrated that glioma cells varied in their susceptibility to HSV-mediated cytotoxicity and that cultured astrocytes were two to three orders of magnitude less susceptible to killing than were malignant glia; and (d) scid mice, which received 0.5 or 5 x 10(6) plaque-forming units of R4009, either were coinoculated at the time of intracranial transplantation with 106 U251MG or D-54MG human glioma cells or received the cells intratumorally 5 days after tumor induction and experienced significant increases in median survivals, with no histopathological indication of an infectious encephalitic process. Genetically engineered gamma(1)34.5- HSV mutants appear to be a potentially safe biotherapeutic agent for experimental treatment of uniformly fatal malignant brain tumors.

Acyclovir↗
PubMed1997

Assessment of pain in herpes zoster: lessons learned from antiviral trials.

Pain typically accompanies acute herpes zoster and, in a proportion of patients, it persists well beyond rash healing. Pain must therefore be analyzed in trials of antiviral agents in herpes zoster, but different methods have been used to analyze pain in recent published trials. These reports are reviewed and their methodological strengths and weaknesses examined. Based on this review, recommendations for the design and analysis of future trials of antiviral agents in herpes zoster are proposed. The principal recommendation is that antiviral efficacy should be evaluated both by distinguishing post-herpetic neuralgia from acute pain and by considering pain as a continuum. The primary endpoint should address both the prevalence and duration of post-herpetic neuralgia and should be examined in those patients who have post-herpetic neuralgia. Adopting the proposed recommendations in design and analysis of future trials should facilitate comparison across trials of the efficacy of antiviral agents in the treatment of herpes zoster.

Antiviral Agents↗
PubMed1997

Ganciclovir treatment of symptomatic congenital cytomegalovirus infection: results of a phase II study. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.

Congenital cytomegalovirus (CMV) infection occurs in approximately 1% of newborns in the United States. A phase II evaluation was done of ganciclovir for the treatment of symptomatic congenital CMV infection. Daily doses of 8 or 12 mg/kg were administered in divided doses at 12-h intervals for 6 weeks. Clinical and laboratory evaluations sought evidence of toxicity, quantitative virologic responses in urine, plasma drug concentrations, and clinical outcome. A total of 14 and 28 babies received 8 and 12 mg/kg/day, respectively. Five additional babies received ganciclovir on a compassionate plea basis. Significant laboratory abnormalities included thrombocytopenia (< or = 50,000/mm3) in 37 babies and absolute neutropenia (< or = 500 mm3) in 29 babies. Quantitative excretion of CMV in the urine decreased; however, after cessation of therapy, viruria returned to near pretreatment levels. Hearing improvement or stabilization occurred in 5 (16%) of 30 babies at 6 months or later, indicating efficacy.

Alanine Transaminase↗
PubMed1997

New therapeutic approaches to the alphaherpesvirus infections.

The character of diseases caused by alphaherpesviruses has changed over the last decade. The severity of disease and the frequency of acyclovir resistance has increased with the increase in the number of immunocompromised patients. Compounding the trend towards more virulent herpes disease is the current emphasis towards outpatient management of many diseases. Much of the current antiviral research focuses on providing drugs with (i) improved oral bioavailability and pharmacokinetics which permit less frequent oral or topical dosing for suppressive treatment of herpes simplex virus (HSV) infections, (ii) different mechanisms of action for synergic effects in treating resistant HSV infections in the immunocompromised host and (iii) improved efficacy. Future antiviral agents will probably target enzymes or viral factors essential for infection or will inhibit other steps in the viral infection cycle, such as viral entry, protein synthesis or capsid assembly. Medications that augment the immune response constitute another pathway for combating herpes viral infections. Many of the newer experimental agents target essential processes unique to herpesvirus replication and, therefore, potentially have high selectivity.

2-Aminopurine↗
PubMed1997

Antiviral therapy for neonatal herpes simplex virus: a cost-effectiveness analysis.

Each year, about 1,600 infants in the United States are infected with neonatal herpes simplex virus. We conducted a cost-effectiveness analysis of antiviral drug therapy (acyclovir) for three forms of herpes simplex virus infection: skin, ear, and mouth (SEM), central nervous system (CNS), and disseminated multiorgan (DIS) disease. Five levels of patient outcomes were examined (normal, mild, moderate, severe, dead). We obtained information on disease occurrence and survival from clinical trials and historical reviews of untreated newborns. We considered approaches for treating all or any of the forms of the disease and compared them with no use of antiviral drugs. The main measure of effectiveness was lives saved, including those of descendants of survivors. Costs were measured from a societal perspective and included direct medical costs, institutional care, and special education. We used a discount rate of 3% and valued dollars at 1995 levels. We also considered the perspective of a managed care organization. From a societal viewpoint relative to no treatment, antiviral therapy for SEM resulted in a gain of 0.8 lives and a cost reduction of $78,601 per case. For the treatment of CNS and DIS disease, antiviral therapy saved more lives but at increased cost, with respective marginal costs per additional life saved of $75,125 and $46,619. From a managed care perspective, antiviral therapy is more cost-effective than from a societal viewpoint because costs of institutional care and special education are not the responsibility of managed care organizations. Development of at-home therapies will further improve the cost-effectiveness of antiviral therapy for neonatal herpes simplex virus infection.

Acyclovir↗
PubMed1997

Treatment of viral infections during pregnancy and the neonatal period.

Over the past 15 years, successful antiviral therapy of herpes simplex virus (HSV) infection has emerged with safe therapeutics. Despite the major impact of acyclovir on the severity of HSV infection, morbidity and mortality from neonatal herpes exist. The development of therapeutics that impact on the natural history of HIV and AIDS just now are being realized, nearly a decade after the first beneficial effects of therapy were reported. Early investigations of antiviral agents in pregnant women and children must occur more promptly as the field of antiviral therapy advances. Improved therapeutics are likely to emerge over the next decade for both pregnant women and their offspring.

Antiviral Agents↗
PubMed1997

The effects of modifying proficiency testing materials on thyroid function test results. A College of American Pathologists Ligand Assay Survey Study.

OBJECTIVE: To gain insight on the matrix effects, and possible clinical implications, resulting from diluting and concentrating proficiency testing survey material used for the measurement of thyroid function tests. DESIGN: To the standard set of five proficiency survey samples, three supplementary "Wildcard" samples were added. These additional samples were manufactured by overfilling and underfilling vials prior to lyophilization so as to vary the thyroxine-binding protein concentrations. Survey participants measured thyroxine, free thyroxine, and the triiodothyronine uptake and related tests on the Wildcard samples. In addition, free thyroxine indices were calculated. SETTING: The first mailing of the 1995 College of American Pathologists (CAP) Ligand Assay--Series 1 Survey. MAIN OUTCOME MEASURES: Results obtained from the regular set of survey samples and the Wildcard set were compared to values expected by the laws of conservation of matter and mass action. PARTICIPANTS: The approximately 2000 participants of the first mailing of the 1995 CAP Ligand Assay--Series 1 Survey. RESULTS: Numerous assays systems did not give the predicted results, including all of the single-step radioimmunoassays for free thyroxine and over three quarters of free thyroxine index determinations. CONCLUSIONS: Varying the dilution of proficiency survey material produced results that were not predicted by the laws of conservation of matter and of mass action. Although these observations may have been the result of matrix effects, one cannot rule out the possibility that certain thyroid assays may not work in clinical situations having abnormal thyroxine-binding protein concentrations.

Data Collection↗
PubMed1996

The application of genetically engineered herpes simplex viruses to the treatment of experimental brain tumors.

Due to lack of effective therapy, primary brain tumors are the focus of intense investigation of novel experimental approaches that use vectors and recombinant viruses. Therapeutic approaches have been both indirect, whereby vectors are used, or direct to allow for direct cell killing by the introduced virus. Genetically engineered herpes simplex viruses are currently being evaluated as an experimental approach to eradicate malignant human gliomas. Initial studies with gamma (1)34.5 mutants, R3616 (from which both copies of the gamma (1)34.5 gene have been deleted) and R4009 (a construct with two stop codons inserted into the gamma (1)34.5 gene), have been assessed. In a syngeneic scid mouse intracranial tumor model, recombinant herpes simplex virus can be experimentally used for the treatment of brain tumors. These viruses and additional engineered viruses were subsequently tested in human glioma cells both in vitro and in vivo. Using a xenogeneic scid mouse intracranial glioma model, R4009 therapy of established tumors significantly prolonged survival. Most importantly, long-term survival was achieved, with histologic evidence that R4009 eradicated intracranial tumors in this model. Furthermore, the opportunity to evaluate gamma (1)34.5 mutants that have enhanced oncolytic activity, e.g., R8309 where the carboxyl terminus of the gamma (1)34.5 gene has been replaced by the murine homologue, MyD116, are considered.

Adenoviridae↗
PubMed1996

Acyclovir with and without prednisone for the treatment of herpes zoster. A randomized, placebo-controlled trial. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.

OBJECTIVE: To determine the effect of acyclovir and prednisone treatment of herpes zoster on chronic pain and quality-of-life outcomes. DESIGN: Randomized, double-blind, placebo-controlled study with a 2 x 2 factorial design. SETTING: 15 university hospitals or affilliated clinics. PATIENTS: 208 immunocompetent patients older than 50 years of age who had localized herpes zoster that developed less than 72 hours before study enrollment. INTERVENTION: Acyclovir or a matched placebo was administered orally, 800 mg five times daily, for 21 days. Prednisone or a matched placebo was administered orally at 60 mg/d for the first 7 days, 30 mg/d for days 8 to 14, and 15 mg/d for days 15 to 21. The four treatments regimens given were acyclovir plus prednisone; acyclovir plus prednisone placebo; prednisone plus acyclovir placebo; and placebos for both acyclovir and prednisone. MEASUREMENTS: Patients were monitored daily for the first 28 days for lesion healing, resolution of pain, return to usual activity, and return to uninterrupted sleep. Monitoring was then done monthly for 6 months. Patients documented analgesic requirements each day, and adverse events and laboratory abnormalities were recorded at each clinical visit. An intention-to-treat analysis was used. RESULTS: Patients were randomly allocated to receive one of the four regimens. Demographic characteristics were similar for each group. Time to total crusting and healing was accelerated for patients receiving acyclovir plus prednisone compared with patients receiving two placebos; the risk ratios were 2.27 (95% Cl, 1.46 to 3.55) for total crusting and 2.07 (Cl, 1.26 to 3.38) for healing. Similarly, compared with the placebo group, patients receiving acyclovir plus prednisone had accelerated time to cessation of acute neuritis (risk ratio, 3.02 [Cl, 1.42 to 6.41]), time to return to uninterrupted sleep (risk ratio, 2.12 [Cl, 1.25 to 3.58]); time to return to usual daily activity (risk ratio, 3.22 [Cl, 1.92 to 5.40]); and time to cessation of analgesic therapy (risk ratio, 3.15 [Cl, 1.69 to 5.89]). In the acyclovir plus prednisone group, resolution of pain during the 6 months after disease onset did not statistically differ from that in the other groups. No important clinical or laboratory adverse events occurred in any group. CONCLUSIONS: In relatively healthy persons older than 50 years of age who have localized herpes zoster, combined acyclovir and prednisone therapy can improve quality of life.

Acyclovir↗
PubMed1996

A method for detection of HHV-6 antigens and its use for evaluating antiviral drugs.

A simple and reproducible method for detection of human herpesvirus 6 (HHV-6) antigens was developed using a dot blot assay in order to assess virus titer and to evaluate the effect of antiviral drugs against HHV-6. The titer of virus stocks obtained by the dot blot assay was the same as that determined by an immunofluorescence assay (IFA). This method was then applied to evaluate the effect of several antiviral drugs against HHV-6, including phosphonoformic acid (PFA), 9-(2-hydroxyethoxymethyl)guanine (ACV), 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG) and (S)-1-[(3-hydroxy-2-phosphonylmethoxy)propyl]cytosine [(S)-HPMPC]. The end-point concentrations (EPC, which was determined visually) of DHPG and (S)-HPMPC were approximately 1 microgram/ml. These drugs were more effective than the others which had EPCs of approximately 16 micrograms/ml each. The EPC values of four drugs were almost similar to EC90 values determined by measuring density of each dot blot. Thus, the EPC values can be utilized to determine the efficacy of these drugs in the inhibition of HHV-6 replication. The block in virus replication was not due to toxic effect of these drugs on cord blood mononuclear cells (CBMCs). These results suggest that a dot blot method which detects HHV-6 antigens can be useful for titrating virus yield and evaluating antiviral drugs against HHV-6 replication.

Antigens, Viral↗