Search PubMed⌕ Search

Biomedical subjects

S Broder

Publications and source records attributed to S Broder.

At least 55 records · Page 3Linked to original sources
PubMed1992

Effects of bone marrow stimulatory cytokines on human immunodeficiency virus replication and the antiviral activity of dideoxynucleosides in cultures of monocyte/macrophages.

Cells of the monocyte lineage are important targets for the replication of human immunodeficiency virus (HIV). Our group and others have previously shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates HIV replication in monocyte/macrophages, but that it also enhances the anti-HIV activity of 2',3'-dideoxy-3'-azidothymidine (AZT). In the present study, we have explored the effects of other bone marrow stimulatory cytokines on the replication of HIV and on the anti-HIV activity of certain dideoxynucleosides in human peripheral blood monocyte/macrophages (M/M). Like GM-CSF, macrophage CSF (M-CSF) enhanced HIV replication in M/M. In contrast, granulocyte CSF (G-CSF) and erythropoietin (Epo) had no such effects. The anti-HIV activity of zidovudine (AZT) was increased in M/M exposed to GM-CSF. In contrast, the anti-HIV activity of AZT was unchanged in M/M exposed to M-CSF, and the activities of 2',3'-dideoxycytidine (ddC) and 2',3'-dideoxyinosine (ddl) were unchanged or slightly diminished in M/M stimulated with GM-CSF or M-CSF. These differential activities of AZT and ddC were paralleled by differential effects of the cytokines on the anabolism of these drugs to their active 5'-triphosphate moieties. GM-CSF increased the levels of AZT-5'-triphosphate (at least in part through an increase in thymidine kinase activity) and overall induced an increase in the ratio of AZT-5'-triphosphate/thymidine-5'-triphosphate. In contrast, M-CSF-induced increases in AZT-5'-triphosphate were roughly matched by increases in thymidine-5'-triphosphate. Also, GM-CSF- or M-CSF-induced increases in the levels of ddC-5'-triphosphate were associated with parallel increases in the levels of deoxycytidine-5'-triphosphate (the physiologic nucleoside that competes at the level of reverse transcriptase), so that there was relatively little net change in the ddC-5'-triphosphate/deoxycytidine-5'-triphosphate ratio. Thus, bone marrow stimulatory cytokines may have a variety of effects on HIV replication and on the activity and metabolism of dideoxynucleosides in M/M.

Antiviral Agents↗
PubMed1992

Oncology.

Explore the source record for details and available documents.

Breast Neoplasms↗
PubMed1992

Synthesis and anti-HIV activity of isonucleosides.

A series of isomeric 2',3'-dideoxynucleosides which contains a modified carbohydrate moiety has been prepared. This class of compounds was designed to mimic the activity of known anti-HIV dideoxynucleosides, while imparting enhanced chemical and enzymatic stability. Isonucleosides containing the standard heterocyclic bases (A, C, G, T) were synthesized via nucleophilic addition of the base to an isomeric sugar unit. Modified derivatives were generated by manipulation of the intact isonucleoside. Two of the compound prepared, iso-ddA (1) and iso-ddG (6), exhibit significant and selective anti-HIV activity, as well as beneficial hydrolytic stability.

Antiviral Agents↗
PubMed1992

A pilot study of 2',3'-dideoxyinosine for the treatment of chronic hepatitis B.

The nucleoside analog 2',3'-dideoxyinosine, currently being used to treat patients infected with the human immunodeficiency virus, has been shown to inhibit viral replication in certain cell culture systems of hepatitis B virus and the duck model of chronic hepatitis B infection. We studied the effect of dideoxyinosine on viral replication in patients with chronic hepatitis B. In the initial dose-finding phase, patients received sequential 2-wk courses of dideoxyinosine in escalating doses of 3, 6 and 9 mg/kg/day. In the second, long-term treatment phase, patients received dideoxyinosine at a dose of 9 mg/kg/day for 12 wk. Dideoxyinosine was given orally in three divided doses. The effects of dideoxyinosine on hepatitis B were assessed by serial measurements of ALT, hepatitis B virus DNA and DNA polymerase activity in serum. Six patients completed the dose-finding phase, and five patients continued into the long-term treatment phase. No significant differences were seen in serum aminotransferases, hepatitis B virus DNA levels or DNA polymerase activity at any time during treatment when compared with pretreatment levels. All patients remained positive for HBeAg during treatment and during 6 mo of follow-up. Thus at the doses tested, dideoxyinosine had no appreciable effect on viral replication in patients with chronic hepatitis B.

Adult↗
PubMed1992

The immunology of HIV infection: implications for therapy.

It is known that antiretroviral drugs can induce immunologic improvement in patients with acquired immunodeficiency syndrome (AIDS) and other manifestations of HIV infection. However, the improvements so attained are often partial and transient. This may result from a number of factors, including incomplete inhibition of human immunodeficiency virus (HIV) replication by available agents, the development of viral drug resistance, the effect of cytokines, or thymic damage. An understanding of this problem may be important in further development of AIDS therapies. It will also be important to learn how to best assess the response to various therapies. In this regard, the CD4 count is evolving as a mortality risk indicator in AIDS and as such may find utility in assessing new therapeutic approaches. We have observed that in a cohort of gay men receiving antiretroviral therapy in a research environment, nearly all deaths occurred in individuals with fewer than 50 CD4 cells/mm3. However, the relationship between the CD4 count and the hazard of dying may be influenced by a number of factors (e.g., active intravenous drug use, extreme poverty, etc.), and further studies are needed to define the relationship between CD4 and clinical endpoints under a variety of conditions.

HIV Infections↗
PubMed1992

Plasma HIV-1 viremia in HIV-1 infected individuals assessed by polymerase chain reaction.

We established a method to estimate the amounts of HIV-1 particles in plasma from patients with HIV-1 infection by using polymerase chain reaction (PCR) following reverse transcription (RT) of viral RNA (RNA-PCR) and assessed the potential usefulness of this approach to monitor the changes of viral load in patients with AIDS or AIDS-related complex (ARC) receiving 2',3'-dideoxyinosine (ddI). Plasma samples were obtained from 77 patients with HIV-1 infection (49 AIDS/ARC and 28 asymptomatic seropositives). Following ultracentrifugation of plasma, RNA was extracted from the pelleted virus and subjected to RT and PCR. The number of HIV-1 virus particles in each sample was determined using known amounts of HIV-1 DNA as reference control for PCR. The current plasma RNA-PCR technique quantitatively detected HIV-1 particles in plasma from 76 of 77 (98.7%) HIV-1-infected individuals examined. The numbers of HIV-1 particles in plasma from patients with AIDS or ARC were markedly higher than those in plasma from asymptomatic seropositive individuals (p less than 0.0001). Higher levels of plasma HIV-1 particle numbers were detected in individuals with lower CD4+ T cell counts. Patients (n = 10) who received oral ddI at doses greater than or equal to 6.4 mg/kg/day for 8 to 14 weeks had a profound decrease in plasma HIV-1 particle numbers (p = 0.0051). Patients (n = 7) receiving ddI for 45 to 71 weeks also had a decrease (p = 0.018). It should be noted, however, that more research is required to evaluate the usefulness of this technique in assessing the disease status and monitoring the activity of antiretroviral therapy.

Base Sequence↗
PubMed1992

Oligodeoxyribonucleotide phosphorothioate fluxes and localization in hematopoietic cells.

An antisense oligonucleotide phosphorothioate, previously shown to inhibit HIV-1 viral expression in chronically infected H9 cells, was fluorescently labeled to study oligonucleotide fluxes and localization within living cells. Observations based on flow cytometry and fluorescence microscopy show the following: within around 0.5-2 h, an apparent steady-state distribution of the oligonucleotide is achieved in which the intracellular oligonucleotide concentration is less than that present in the external medium; following oligonucleotide uptake and resuspension of the cells in oligonucleotide-free medium, an oligonucleotide efflux, with a time constant similar to that for uptake, is observed (although a significant fraction of the phosphorothioate remains within the cell); cellular uptake as a function of the external oligonucleotide concentration is nonlinear, being more efficient at lower concentrations (less than 2 microM); and a predominant oligonucleotide localization within the cell nucleus and perinuclear organelles is observed.

Base Sequence↗
PubMed1992

The pathogenesis of AIDS lymphomas: a foundation for addressing the challenges of therapy and prevention.

The association between AIDS and a spectrum of malignancies relates to chronic, profound defects in both cellular and humoral mechanisms of immune surveillance. Ironically, as AIDS patients live longer in response to increasingly effective antiretroviral therapies, the incidence of AIDS-related malignancies will continue to rise. The emergence of non-Hodgkin's lymphomas (NHL) as a major sequela of HIV infection bears a striking relationship to depletion of CD4 lymphocytes, particularly below 50/mm3. The ability to interfere early in the course of active HIV infection with additional mechanisms that may promulgate transformed cell hyperproliferation and clonal expansion--growth factors, HIV itself or other viruses (Epstein-Barr, in particular), aberrant oncogene or tumor suppressor genes expression, factors that induce genetic instability or DNA damage or alter host or viral genome repair--might decrease the occurrence or prolong the time to development of AIDS-related malignancies. The development of antiretroviral strategies that confer long-term suppression of HIV activity and relative preservation of immune function are essential to the ultimate prevention of malignancies that arise as a consequence of HIV-induced immunosuppression.

Actuarial Analysis↗
PubMed1992

Correlations between the in vitro and in vivo activity of anti-HIV agents: implications for future drug development.

Some 10 years after the first recognition of acquired immunodeficiency syndrome (AIDS) as a new syndrome, we have identified a number of molecular targets to interrupt the replicative cycle of human immunodeficiency virus (HIV), the causative agent. A number of dideoxynucleosides have been identified as having anti-HIV activity in vitro, and several of these have been found to have clinical activity in patients. In contrast, while a number of agents have been found to block viral binding to the target cell in vitro, these agents have generally not shown clear-cut evidence of clinical activity. Agents which act at a variety of steps in the HIV replicative cycle are now under development, and it is likely that we will have an increased armamentarium to fight this disease in the near future.

Acquired Immunodeficiency Syndrome↗
PubMed1991

CD4 count and the risk for death in patients infected with HIV receiving antiretroviral therapy.

OBJECTIVE: To investigate the relation between CD4 count and the immediate hazard of dying in patients receiving zidovudine (azidothymidine [AZT])-based antiretroviral therapy. SETTING: A research hospital that recruits patients from the entire United States. DESIGN: Retrospective analysis of a cohort of patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex participating in long-term zidovudine-based antiretroviral protocols. PATIENTS: Fifty-five patients with human immunodeficiency virus (HIV) infection and either AIDS or severe AIDS-related complex who were followed for as many as 4 years while they received antiretroviral therapy. MEASUREMENTS: CD4 counts were measured. MAIN RESULTS: Ten patients are known to be alive and 1 was lost to follow-up. Of the 44 patients who are known to have died, the CD4 range was known within 6 months of death in 41. All but 1 of these 41 assessable deaths occurred in patients whose CD4 counts were known to have fallen below 50 CD4 cells/mm3 (P less than 10(-10)). The hazard of dying in the cohort ranged from 0 deaths/patient-month (95% CI, 0 to 0.008 deaths/patient-month) in patients with 200 or more CD4 cells/mm3 to 0.07 deaths/patient-month (CI, 0.050 to 0.094 deaths/patient-month) in patients with fewer than 50 CD4 cells/mm3. For the patients who died and whose cases were assessable, the mean of the last three CD4 counts obtained before death was 7.7 CD4 cells/mm3 (CI, 0.9 to 63.3 cells/mm3). The median survival of patients once their CD4 counts fell below 50 CD4 cells/mm3 was 12.1 months (CI, 7.2 to 19.4 months). CONCLUSIONS: In a carefully followed cohort treated with zidovudine-based antiretroviral therapy, nearly all deaths occurred in patients with fewer than 50 CD4 cells/mm3. These findings may have implications in the monitoring of patients with AIDS and in the use of CD4 count as a clinical trials end point for the antiretroviral therapy of HIV infection.

CD4-Positive T-Lymphocytes↗
PubMed1991

Oncology.

Explore the source record for details and available documents.

Genetic Therapy↗
PubMed1991

Projections of the incidence of non-Hodgkin's lymphoma related to acquired immunodeficiency syndrome.

Advances in antiretroviral therapy and treatment or prophylaxis against opportunistic infection have resulted in prolongation of the survival of patients with acquired immunodeficiency syndrome (AIDS). Previous research has demonstrated an association between AIDS and risk of non-Hodgkin's lymphoma (NHL). In addition to the approximately 3% of individuals found to have NHL at the time of AIDS onset, others continue to develop NHL following AIDS diagnosis. Data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute demonstrated a sharply increasing incidence of NHL among men in the age range 20-49 years since 1983 in the United States. Based on new data on the risk of NHL following AIDS diagnosis, on estimates of improved survival following AIDS diagnosis, and on projections of future AIDS incidence, we considered four sets of assumptions and estimated the number of AIDS-related NHL cases in 1992 to be between 2900 and 9800. Three of these projections were higher than the estimate of 4700 cases obtained by linear extrapolation of SEER incidence trends. These projections of AIDS-related NHL incidence suggest that between 8% and 27% of all NHL cases that occur in the United States in 1992 will arise as a consequence of infection with the human immunodeficiency virus (HIV), imposing a substantial health care burden. More research into the pathogenesis of lymphoma and new approaches to antiretroviral and antilymphoma therapy will be necessary to prevent and treat this formidable complication of infection with HIV.

Acquired Immunodeficiency Syndrome↗