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Biomedical subjects

R J Whitley

Publications and source records attributed to R J Whitley.

At least 91 records · Page 5Linked to original sources
PubMed1995

The data and safety monitoring board and acquired immune deficiency syndrome (AIDS) clinical trials.

The urgency of the Acquired immune deficiency syndrome (AIDS) epidemic has mandated that multiple therapeutic approaches be developed and that these approaches be evaluated through clinical trials. To oversee these trials, the National Institute of Allergy and Infectious Diseases (NIAID) has created three large clinical trial programs monitored by a Data and Safety Monitoring Board (DSMB). For each clinical trial, this Board uses a standardized approach employing contemporary biostatistical, medical, and ethical principles. The DSMB is responsible for reviewing interim data on clinical trial performance, treatment safety and efficacy, and overall study progress. If interim results provide convincing evidence of either excessive adverse effects or significant treatment benefit, the DSMB may recommend early termination of the trial to the NIAID and the study investigators. The responsibility, organization, and operating procedures of this DSMB are presented and illustrated through three clinical trials sponsored by NIAID and monitored by the Board. The rationale and operational model for the DSMB may be a useful example for the development of similar review processes in other HIV clinical trial settings.

Advisory Committees↗
PubMed1995

Herpes simplex virus infections of the central nervous system: therapeutic and diagnostic considerations.

Herpes simplex virus infections of the central nervous system remain a significant cause of morbidity and mortality, in spite of safe and efficacious antiviral therapy. Advances in the treatment of neonatal herpes and herpes simplex encephalitis with acyclovir have improved outcome. The application of polymerase chain reaction has allowed for the prompt and specific diagnosis of herpes simplex virus infections of the brain. This review summarizes our current knowledge on the pathogenesis, diagnosis, and treatment of herpes simplex virus infections of the brain. Opportunities for the future will be defined.

Acyclovir↗
PubMed1995

Human herpesvirus 6 is associated with focal encephalitis.

Human herpesvirus 6 (HHV-6) is a cause of roseola infantum. Recent reports associate HHV-6 with cases of encephalitis; however, conclusive etiologic data do not exist. We evaluated clinical data and laboratory specimens obtained from patients with focal encephalitis of unknown etiology. Cerebrospinal fluid (CSF) specimens were tested by polymerase chain reaction for the presence of HHV-6 DNA. Selected samples were analyzed by DNA sequencing. We detected HHV-6 DNA in the CSF of nine of 138 patients. DNA sequencing revealed that group B strains of HHV-6 were present in those specimens that were analyzed. No significant differences could be demonstrated in clinical presentation, laboratory findings, or neurodiagnostic imaging results between the nine patients with confirmed HHV-6 infection and the 129 patients without evidence of HHV-6 infection. Neurological outcome for the nine HHV-6-infected patients varied from complete recovery without neurological deficit to death. Further prospective study is warranted.

Adult↗
PubMed1995

Herpesvirus infections in persons infected with human immunodeficiency virus.

Herpesviruses are among the most common causes of infections of humans. Viruses in this family share the unique biological property of being able to establish latency and to recur. Furthermore, chronic excretion of virus is not uncommon. In the immunocompromised host, including persons with human immunodeficiency virus (HIV) infection, herpesvirus disease can be particularly severe, resulting in chronic, persistent, active infection and, in some cases, life-threatening disease. The most pathogenic of the herpesviruses in patients with AIDS include herpes simplex viruses, human cytomegalovirus, and varicella-zoster virus. Disease caused by Epstein-Barr virus, particularly opportunistic malignancies, has been recognized. A new herpesvirus that is associated with Kaposi's sarcoma was recently described. On the other hand, disease caused by human herpesviruses 6 and 7 in persons infected with HIV remains to be unequivocally recognized. Prevention of exposure to herpesviruses, disease, and recurrence requires different measures than those for some of the other opportunistic infections in HIV-infected patients; this is because herpesvirus disease develops in most of these individuals as a result of reactivation rather than primary infection. Thus, approaches to the prevention and control of herpesvirus infections must be individualized according to both the type of virus as well as the type of infection (i.e., primary or recurrent). We discuss recommended measures for the prevention and control of these infections.

HIV Infections↗
PubMed1995

Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.

Isolation of herpes simplex virus (HSV) from brain tissue after biopsy has been considered the reference standard for the diagnosis of herpes simplex encephalitis (HSE). During the evaluation of antiviral treatment of HSE, cerebrospinal fluid (CSF) was obtained from patients with clinical disease indicative of HSE who underwent diagnostic brain biopsy. HSV DNA was detected by polymerase chain reaction (PCR) in CSF of 53 (98%) of 54 patients with biopsy-proven HSE and was detected in all 18 CSF specimens obtained before brain biopsy from patients with proven HSE. Four of 19 CSF specimens were positive after 2 weeks of antiviral therapy. Positive results were found in 3 (6%) of 47 patients whose brain tissue was culture-negative. Detection of HSV DNA in the CSF correlated significantly with age and focal radiographic findings. Thus, PCR detection of HSV DNA should be the standard for diagnosis of HSE.

Base Sequence↗
PubMed1995

Sorivudine: a promising drug for the treatment of varicella-zoster virus infection.

Sorivudine provides a unique nucleoside analog with significantly enhanced both in vitro and in vitro activity and enhanced oral bioavailability. Early indications from controlled studies indicate that sorivudine therapy is superior to acyclovir for the treatment of localized zoster in individuals with HIV infection and adults with chicken pox. However, these studies await peer evaluation. Importantly, recent experience in Japan indicates administration of sorivudine with 5-fluorouracil (5-FU) is contraindicated. Sorivudine inhibits dihydropyrimidine dehydrogenase, which is required for the metabolism of 5-FU. As a consequence, toxic levels of 5-FU accumulate in the plasma and have led to the deaths of nearly 30 patients in Japan. One might question, as these data unfold, the relative value of drugs with such enhanced in vitro activity and oral bioavailability as compared with standard therapeutic agents. Should accelerated healing occur, but not as dramatically as would have been anticipated from the in vitro data, unique approaches to the management of herpes zoster will need to be developed if further improvement is desired. Regardless, sorivudine appears superior to acyclovir for acceleration of cutaneous healing and, importantly, can be administered once daily in significantly smaller concentrations. These findings in and of themselves should allow for licensure of the compound in other developed societies.

Antiviral Agents↗
PubMed1994

Herpes simplex virus infections of women and their offspring: implications for a developed society.

Herpes simplex virus infections of humans have been known since ancient times. Contemporary society has witnessed a series of devastating manifestations of herpes simplex virus infections--namely, genital herpes simplex virus infection and neonatal herpes simplex virus infection. With the evolution of society, particularly advances in birth control and increasing promiscuity, the seroprevalence of herpes simplex virus type 2 infections has increased worldwide, however, more so in developed societies. As a consequence, individuals of child-bearing age are at risk for either reactivation of herpes simplex virus at termination of gestation or acquisition of a new primary infection at that time. The consequences of vertical transmission of herpes simplex virus from mother to child, resulting in neonatal herpes simplex virus infection, can be devastating. Current efforts, which are directed toward the treatment of neonatal herpes, have established the value of drugs such as vidarabine and acyclovir. However, the real emphasis for future programs is the prevention of herpes simplex virus infections to avoid person-to-person transmission either horizontally or vertically. The development of vaccines directed against herpes simplex virus may be of value toward this end.

Antiviral Agents↗
PubMed1994

A rapid protein A binding radioimmunoassay for the evaluation of antiviral agents.

A simple, rapid and quantitative protein A binding radioimmunoassay (RIA) was developed to screen and evaluate antiviral drugs against human cytomegalovirus (HCMV) replication. It was found that (S)-1-[(3-hydroxy-2-phosphonylmethoxy)propyl]cytosine (HPMPC) and human gamma-interferon (IFN) were more effective than 9-[(1-3-dihydroxy-2-propoxy)methyl]guanine (DHPG) and other IFNs against HCMV replication in human fibroblast cells. The block in virus replication was not due to toxic effect of these compounds on human fibroblast cells. The results were in good agreement with those of other workers. The results indicate that protein A binding RIA can be useful for rapid and quantitative screening of compounds effective against HCMV replication.

Antiviral Agents↗
PubMed1994

Neonatal herpes simplex virus infections: is there a role for immunoglobulin in disease prevention and therapy?

Neonatal herpes simplex virus infections cause significant morbidity and mortality among infected babies, despite the availability of antiviral therapy. These infections manifest in one of three forms: skin, eye, and mouth involvement; encephalitis; or disseminated infection. The latter two forms of disease account for more than 50% of babies with neonatal herpes and are associated with mortality and severe morbidity rates that exceed 75% in infected children. Thus future therapeutic efforts must be directed toward improved disease outcome. One such effort is the evaluation of immunoglobulin products (humanized monoclonal antibodies, human monoclonal antibodies and hyperimmune globulin) as part of a concomitant therapeutic regimen for babies with encephalitis and disseminated infection. The logic for such an approach becomes especially apparent for babies with disseminated disease because little transplacental maternal antibody is received at the time of birth. Thus concomitant administration of antiviral therapy with antibody may improve disease outcome.

Acyclovir↗
PubMed1993

A short-term clinical evaluation of L-697,661, a non-nucleoside inhibitor of HIV-1 reverse transcriptase. L-697,661 Working Group.

BACKGROUND: The non-nucleoside reverse transcriptase inhibitors are novel antiretroviral agents with selective activity in vitro against human immunodeficiency virus type 1 (HIV-1). They act through direct inhibition of reverse transcriptase and are not incorporated into DNA. METHODS: We evaluated a pyridinone non-nucleoside reverse transcriptase inhibitor, L-697,661, in separate six-week double-blind trials in patients with HIV-1 infection whose CD4 counts ranged from 200 to 500 cells per cubic millimeter (68 patients) or less than 200 cells per cubic millimeter (67 patients). Eligible patients were randomly assigned to receive L-697,661 orally in one of three doses (25 mg twice a day, 100 mg three times a day, or 500 mg twice a day) or zidovudine (100 mg five times a day). Clinical and laboratory assessments were performed weekly. Viral isolates were obtained from a subgroup of patients before and after treatment and were evaluated for in vitro sensitivity to L-697,661. RESULTS: Both L-697,661 and zidovudine were well tolerated. Transient increases in CD4 counts were noted in the patients with fewer than 200 CD4 cells per cubic millimeter who received the two higher doses of L-697,661, but not in those who received the lowest dose or zidovudine. Patients who received L-697,661 had rapid, dose-related decreases in plasma p24 antigen levels. However, this response virtually disappeared after six weeks in some patients receiving L-697,661, coincidently with the emergence of resistant viruses. This change in susceptibility was more frequent among patients receiving the higher doses of L-697,661 and was associated with amino acid substitutions at positions 103 and 181 in the HIV-1 reverse transcriptase gene. CONCLUSIONS: L-697,661 is safe and well tolerated and has significant dose-related activity against HIV-1. However, resistant strains of the virus emerge rapidly and may limit the effectiveness of non-nucleoside reverse transcriptase inhibitors as monotherapy for HIV-1 infection.

Adult↗
PubMed1993

Neonatal herpes simplex virus infections.

Neonatal herpes simplex virus infections are a common problem in the United States, occurring at an incidence of one in approximately 3,500 deliveries. In the absence of antiviral therapy significant morbidity and mortality is attendant with disease. Disease manifestations in the newborn include multiorgan involvement (disseminated disease), encephalitis, and/or infection limited to the skin, eye, or mouth. These three broad classifications provide distinctions in severity of disease for evaluation of outcome following antiviral therapy. The availability of antiviral therapy for life-threatening disease, particularly that which is disseminated or involves the brain, has been of particular benefit for children with neonatal herpes. Both acyclovir and vidarabine have proven effective in the management of neonatal herpes simplex virus infection. With current therapeutic modalities, mortality from disease localized to the skin, eye, and mouth is virtually non-existent, yet a few children (approximately 5%) are still at risk for a long-term neurologic sequelae. For babies with encephalitis, the mortality has been reduced to approximately 15% and nearly 50% of survivors develop normally 3 years after treatment. Outcome with disseminated infection is of less value as mortality remains high (50%), but the number of survivors who develop normally is approximately 85%. The introduction of new antivirals with enhanced lipophilicity and, potentially, greater activity in the central nervous system may further improve outcome from this devastating disease.

Acyclovir↗
PubMed1993

Antiviral effect of the extract of culture medium of Lentinus edodes mycelia on the replication of herpes simplex virus type 1.

An extract of culture medium of Lentinus edodes mycelia, JLS-S001, significantly blocked the release of infectious herpes simplex virus type 1 (HSV-1) from African green monkey kidney cells. The block in replication was not due to the effect of JLS-S001 on the adsorption and penetration of HSV-1 to the monkey kidney cells. This observation was supported by the fact that JLS-S001 had no significant effect on the expression of virus-specific nucleocapsid proteins in the treated cells. Furthermore, electron microscopy demonstrated the presence of nucleocapsids within the nuclei of the infected and JLS-S001-treated cells. However, the expression of glycoproteins B, C, D, E and I was reduced in the JLS-S001-treated cells. These results suggested that JLS-S001 blocked HSV-1 replication at a late stage in virus replication cycle probably in the assembly and budding of nucleocapsids and subsequent egress from the treated cells.

Adsorption↗
PubMed1993

Diabetes insipidus associated with symptomatic congenital cytomegalovirus infection.

We report five infants with congenital cytomegalovirus infection in whom diabetes insipidus developed before initiation of treatment with ganciclovir. Four of five infants required treatment with desmopressin. Magnetic resonance imaging of the brain showed no destruction of the hypothalamus or pituitary gland in any infant. Cortisol levels and results of thyroid function studies were normal in all infants.

Cytomegalovirus Infections↗
PubMed1993

Evaluation of new anti-infective drugs for the treatment of infection with human immunodeficiency virus. The European Working Party of the European Society of Clinical Microbiology and Infectious Diseases.

This guideline describes the preclinical documentation required for a new drug active against human immunodeficiency virus (HIV) and offers suggestions regarding the design and implementation of phase 1, 2, and 3 clinical trials. Drugs with a low level of potential toxicity, especially those that are not nucleoside analogues, should be evaluated in healthy individuals who are not infected with HIV before trials in HIV-infected patients commence. The guideline also discusses possible clinical and laboratory end points for efficacy and emphasizes the need for careful validation of all laboratory end points used. The approach of the guideline is deliberately general: more specific recommendations would soon become outdated in this field, which is characterized by extremely rapid developments.

Anti-Infective Agents↗
PubMed1993

A rabbit model for human cytomegalovirus-induced chorioretinal disease.

AD169, a well-characterized laboratory strain of human cytomegalovirus (HCMV), was used to establish an animal model of progressive HCMV chorioretinal disease by injection of 10(5) pfu into the rabbit vitreous. Chorioretinal, vitreous, and pulmonary disease were monitored by HCMV recovery, clinical observation, antigen localization, and histopathology. Vitritis and focal areas of immune cellular infiltrates were seen in inner retinal layers on days 2-4 after inoculation. Disease progressed with more severe vitritis and to involve the outer retinal layers in areas of mixed monocytic cellular infiltrates, retinal destruction, choroidal edema, and congestion. HCMV was recovered from chorioretinal cell sonicate cultures in titers ranging from 10(4) to 10(5) pfu during peak disease, and HCMV antigens were detected focally by immunofluorescence in retinal layers on days 2 and 4 after inoculation. A rabbit model of HCMV chorioretinitis similar to human CMV disease allows investigation of HCMV pathogenesis and new antiviral therapies and evaluation of immune system modulation of the HCMV ocular infection.

Animals↗
PubMed1993

Replication, establishment of latency, and induced reactivation of herpes simplex virus gamma 1 34.5 deletion mutants in rodent models.

Previous studies have shown that a gene mapping in the inverted repeats of the L component of herpes simplex virus, type 1 DNA, designated as gamma (1) 34.5, was dispensable for growth in cells in culture but that the deletion mutant (R3616) and a mutant containing a stop codon (R4009) in each copy of the gene were incapable of replicating in the central nervous systems (CNS) of mice. Restoration of the deleted sequences restored the wild type virus phenotype. We report here that the gamma (1) 34.5 mutant viruses (R3616 and R4009) replicated in the vaginal tract of two different strains of mice and guinea pig, although both viruses were shed at lower titer and for fewer days than the wild type and restored viruses. Both R3616 and R4009 failed to replicate or cause significant pathology in the cornea of Balb/C mice or following intranasal inoculation of Swiss Webster mice. Analyses of sensory trigeminal and dorsal root ganglia innervating the site of inoculation indicated that the incidence of establishment of latency or reactivation from latency by R3616 and R4009 viruses was significantly lower than that determined for mice infected with wild type or restored virus. Thus, selective deletion of gamma (1) 34.5 gene abolished the capacity of the virus to spread from peripheral mucosal sites to the CNS or replicate in the CNS, and diminished the capacity of the virus to replicate at mucosal sites and, subsequently, establish latency, or be able to be reactivated ex vivo. The results of our studies may have direct implications for the development of genetically engineered herpes simplex virus vaccines.

Animals↗