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Biomedical subjects

S Broder

Publications and source records attributed to S Broder.

At least 73 records · Page 4Linked to original sources
PubMed1991

The human costs of cancer and the response of the National Cancer Program.

The three foundations of the National Cancer Program are basic research, clinical trials (in prevention and treatment), and cancer centers. These foundations have supported a great deal of progress against cancer over the past 20 years. Nevertheless, a number of challenges remain, and continued progress will depend on the speed with which research advances can be translated into practical realities. Poverty is a risk factor for cancer incidence and mortality. Thus, a lack of access to the technologies generated by the National Cancer Program can be a force for bringing about differential burdens of cancer in underserved populations.

Humans↗
PubMed1991

The occurrence of opportunistic non-Hodgkin's lymphomas in the setting of infection with the human immunodeficiency virus.

The incidence of non-Hodgkin's lymphoma (NHL) has increased by over 50% in the United States since 1973. There is epidemiologic evidence that some of this increase is the result of AIDS-related lymphoma and that this component is increasing. Prolonged survival in the setting of a variety of immunodeficiency states is associated with an increased incidence of NHL. The development of antiretroviral therapy and improved therapy for the complications of AIDS has resulted in prolonged survival of patients with AIDS. As these patients survive longer with profound immunodeficiency, they have an increased cumulative risk of developing NHL. This may result in even more AIDS-related NHL in the future than predicted from current epidemiological studies. An increased understanding of the pathogenesis of AIDS-related NHL may lead to means of preventing their occurrence. Also, therapies that may prevent immunodeficiency from developing in HIV-infected patients may reduce the likelihood of NHL developing. Current efforts at treating these lymphomas are aimed at preventing the myelosuppression and immunosuppression associated with current regimens, lymphoma relapses within the central nervous system, and the opportunistic infections associated with treatment of these tumors. Ultimately, the best means of preventing the development of these lymphomas is by preventing infection with HIV.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Progress and challenges in the global effort against cancer.

The new decade has given birth to a large number of new concepts in our approach to cancer. The progress in molecular technology that occurred in the 1980's is being transferred in the 1990's to the bedside. The practical clinical application of basic science innovations is aimed at prevention and curative treatment of cancer in all of its forms, and is becoming a central theme of cancer therapeutics. The progress to date reflects a climate that fosters a unity of basic and clinical investigations, for example, where an understanding of tumor genetics or molecular immunoregulation can translate into an innovative clinical approach such as gene transfer therapy. The challenges that we face in this new decade arise in part from progress in certain areas, such as the discovery of natural products that have important antitumor activity but a limited source, or the increasing incidence in AIDS-related lymphomas that has come about from antiretroviral therapy-induced prolongation of survival for AIDS patients. There are critical challenges from a lack of progress in other areas, as well. The challenge of developing curative therapies is surpassed by the need to prevent those cancers before they arise. The challenge of prevention, as exemplified by the link between lung cancer and smoking, is of paramount importance. The ultimate challenge placed before the global oncology community is to ensure that the fruits of modern technology are available to all who need them.

Humans↗
PubMed1991

Pharmacokinetics of 2',3'-dideoxyinosine in patients with severe human immunodeficiency infection. II. The effects of different oral formulations and the presence of other medications.

2',3'-Dideoxyinosine (ddI) has shown activity against human immunodeficiency virus in phase I clinical trials. The drug is rapidly degraded by acid, however, thus raising questions as to the efficiency and reproducibility of its absorption after oral administration. This investigation studies the bioavailability of several oral dosage forms of ddI. When ddI was given to fasting patients as an oral solution with antacid, the bioavailability was 41% +/- 7% (mean +/- SEM). However, when given as buffered tablets, the bioavailability was considerably less (25% +/- 5%). The bioavailability increased slightly when the tablets were given with supplemental antacid (36% +/- 6%). Two enteric-coated preparations had reasonable bioavailability (36% +/- 5% and 26% +/- 5%), but the peak plasma level was much lower and occurred at a much later time than with the oral solution. When ddI was given as a premeasured powder containing sucrose and buffer to be reconstituted by the patient (the "sachet" preparation), the bioavailability was 29% +/- 6%. This was similar to that of the oral solution for this particular group of patients (30% +/- 7%). However, the bioavailability of the sachet was only 17% +/- 4% when administered with food. When the sachet was given to patients receiving ranitidine, no consistent change in bioavailability was noted. Also, no change in ddI pharmacokinetics was noted in patients receiving ganciclovir.

Acquired Immunodeficiency Syndrome↗
PubMed1991

In vitro inhibition of hepatitis B virus replication by 2',3'-dideoxyguanosine, 2',3'-dideoxyinosine, and 3'-azido-2',3'-dideoxythymidine in 2.2.15 (PR) cells.

Hep G2-derived hepatoblastoma cells (2.2.15), which actively produce hepatitis B virus (HBV), were cultured in the presence of 2',3'-dideoxyguanosine (ddG), 2',3'-dideoxyinosine, or 3'-azido-2',3'-dideoxythymidine (AZT). ddG was the most potent agent. It diminished viral replication by up to 95%, as assessed by the amount of episomal HBV DNA, without impairing cellular growth. AZT was the least effective against HBV. Northern blot analysis revealed no apparent difference in the pregenomic viral RNA profile, suggesting that these dideoxynucleosides suppress reverse transcription in the replicative cycle of HBV. The effect of varying the time of drug exposure showed that these agents can suppress HBV replication even when added late in culture. HBV replication in another 2.2.15 cell population of the same lineage was affected by ddG differently, which may enable the investigation of phenotypic or genetic alterations during culture. The present data suggest that some 2',3'-dideoxynucleosides can exert a potent antiviral activity against HBV in vitro, at least under certain circumstances, although the data do not prove that any of these agents have utility in patients with hepatitis.

Blotting, Southern↗
PubMed1991

Targeted therapy of human immunodeficiency virus-related disease.

Since the discovery of human immunodeficiency virus (HIV) as a pathogenic retrovirus linked to acquired immunodeficiency syndrome (AIDS), a number of potentially useful strategies for antiretroviral therapy of AIDS and its related diseases have emerged. One such strategy involves use of the broad family of 2',3'-dideoxynucleosides, to which 3'-azido-2',3'-dideoxythymidine (AZT) belongs. AZT has been shown to reduce the replication of HIV in vivo and to confer significant clinical benefits in patients in both early and advanced stages of infection. Other members of the family, 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddI), and 2',3'-didehydro-2',3'-dideoxythymidine (d4T), have also been reported to be active against HIV in short-term clinical trials. The armamentarium of antiretroviral agents is rapidly growing. Various nonnucleoside agents have recently been identified to be active against HIV in vitro. HIV-1 protease inhibitors are notable as possible new therapies for HIV-1-related diseases. However, we have faced several new challenges in the antiretroviral therapy in AIDS. These include long-term drug-related toxicities; emergence of drug-resistant HIV variants; and development of various cancers, particularly as effective therapies prolong survival. Progress in understanding structure-activity relations and clinical effectiveness will continue with dideoxynucleoside analogs. However, it seems certain that a variety of nonnucleoside analogs affecting multiple steps in viral replication will become available before long, and combination therapies using multiple antiretroviral drugs will be available. Such therapies will exert major effects against the moribidity and mortality caused by HIV.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Inhibitors of IMP dehydrogenase stimulate the phosphorylation of the anti-human immunodeficiency virus nucleosides 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine.

2',3'-Dideoxyadenosine (ddAdo) and its deamination product 2',3'-dideoxyinosine (ddIno) (didanosine) inhibit the replication and infectivity of the human immunodeficiency virus (HIV) in a number of in vitro assay systems. Early clinical studies (phase I) have indicated a role for ddIno in the treatment of patients with severe HIV infection. In the present in vitro study, the formation in human T cells (MOLT-4, ATH8, and CCRF-CEM) of the pharmacologically active metabolite of ddIno and ddAdo, 2',3'-dideoxyadenosine-5'-triphosphate (ddATP), was found to be stimulated 2-4-fold by appropriate concentrations of inosinate dehydrogenase (IMPD) inhibitors such as ribavirin, tiazofurin, and mycophenolic acid. Concomitant with this increase in ddATP formation from ddIno was an increase in anti-HIV activity of this agent when it was combined with ribavirin in the ATH8 cell assay system and with tiazofurin in the MOLT-4 assay system. No change was noted in the intracellular concentration of the corresponding physiological deoxynucleoside-5'-triphosphate, dATP; positive correlation was observed, however, between the increase in ddATP formation from ddIno and the increase in intracellular IMP occurring as a consequence of IMPD inhibition. The results support the hypothesis that the stimulation of ddATP formation seen when ddIno is combined with ribavirin or other IMPD inhibitors is a consequence of an increased concentration of IMP, the major phosphate donor for the initial phosphorylation step in the anabolism of ddIno to ddATP, i.e., ddIno----ddIMP.

Antiviral Agents↗
PubMed1990

NIH conference. Antiretroviral therapy in AIDS.

OBJECTIVE: To review recent developments of antiretroviral therapy for the acquired immunodeficiency syndrome (AIDS) and related disorders. DATA SOURCES, STUDY SELECTION, AND DATA EXTRACTION: An edited and updated summary of a Clinical Staff Conference held 26 October 1988 at the National Institutes of Health. The speakers discussed their own work as well as related work from other groups. DATA SYNTHESIS: The discovery that human immunodeficiency virus (HIV) causes AIDS has permitted the development of rational antiviral therapy for this disease. Various steps in the replicative cycle of HIV can be targeted for intervention. More basic research into the life cycle of HIV is therefore likely to yield new therapeutic approaches. In 1985, nucleoside analogues called dideoxynucleosides were discovered to be potent inhibitors of HIV replication in vitro. Dideoxynucleosides selectively inhibit HIV reverse transcriptase after they are phosphorylated intracellularly to 5'-triphosphates. One dideoxynucleoside, 3'-azido-2',3'-dideoxythymidine (AZT or zidovudine) has been found to prolong the life of patients with AIDS. This drug can partially reverse HIV dementia and decrease short-term progression to AIDS; it has been approved for treating HIV-infected patients with fewer than 500 CD4+ cells/mm3. AZT is only a first step in developing new therapy for AIDS. Its use is associated with toxicities, particularly bone marrow suppression. Several groups have reported the development of AZT-resistant strains of HIV. Other dideoxynucleosides whose toxicity profiles differ from that of AZT have also shown activity against HIV in early clinical studies. Large-scale, randomized trials of these drugs are now under way. Studies have shown that the binding of HIV to CD4 may be blocked by genetically engineered forms of CD4 and that HIV protease may be inhibited by substrate analogues. Protease inhibitors are an excellent area for further study in patients. Antisense oligonucleotide therapy may target the regulatory genes of HIV and is also being considered. CONCLUSION: With these advances, AIDS is gradually changing from an imminently fatal disease to one that can be managed with the judicious use of drugs and biologics. Progress against AIDS will continue, provided that researchers adhere to the principles of controlled trials.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Molecular targets for AIDS therapy.

The development of antiretroviral therapy against acquired immunodeficiency syndrome (AIDS) has been an intense research effort since the discovery of the causative agent, human immunodeficiency virus (HIV). A large array of drugs and biologic substances can inhibit HIV replication in vitro. Nucleoside analogs--particularly those belonging to the dideoxynucleoside family--can inhibit reverse transcriptase after anabolic phosphorylation. 3'-Azido-2',3'-dideoxythymidine (AZT) was the first such drug tested in individuals with AIDS, and considerable knowledge of structure-activity relations has emerged for this class of drugs. However, virtually every step in the replication of HIV could serve as a target for a new therapeutic intervention. In the future, non-nucleoside-type drugs will likely become more important in the experimental therapy of AIDS, and antiretroviral therapy will exert major effects against the morbidity and mortality caused by HIV.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Long-term toxicity/activity profile of 2',3'-dideoxyinosine in AIDS or AIDS-related complex.

To evaluate the long-term toxicity and activity profile of 2',3'-dideoxyinosine (ddI), a potent inhibitor of human immunodeficiency virus (HIV) replication, in vitro. 58 patients with AIDS or AIDS-related complex were studied with additional reference to the effect of previous treatment with zidovudine, and the effect of ddI on HIV-induced cognitive dysfunction. Doses above 9.6 mg/kg per day of ddI were frequently associated with toxicity (peripheral neuropathy, pancreatitis, or hepatitis). Doses of 9.6 mg/kg per day or below were well tolerated for up to 21 months. A subset of patients receiving 3.2-9.6 mg/kg per day of ddI had long-term immunological improvement and reduction of serum HIV p24 antigen. Immunological changes were especially seen in patients who had little previous zidovudine therapy. 5 patients with HIV-induced cognitive impairment improved with ddI. Thus, ddI may have anti-HIV activity at doses which are tolerated for long-term therapy, although pancreatitis could be a life-threatening complication.

AIDS Dementia Complex↗
PubMed1990

Development of non-Hodgkin lymphoma in a cohort of patients with severe human immunodeficiency virus (HIV) infection on long-term antiretroviral therapy.

OBJECTIVE: To describe the incidence of non-Hodgkin lymphoma in a group of patients with symptomatic human immunodeficiency virus (HIV) infection receiving long-term dideoxynucleoside antiretroviral therapy. DESIGN: We examined the records of all patients with the acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex who were entered into three long-term phase I trials of zidovudine (azidothymidine, AZT) or zidovudine-containing regimens at the National Cancer Institute between 1985 and 1987. SETTING: The Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland. PARTICIPANTS: Fifty-five HIV-infected patients with AIDS or severe AIDS-related complex. MEASUREMENTS AND MAIN RESULTS: Eight of fifty-five patients (14.5%; 95% CI, 6.5% to 26.7%) developed a high-grade non-Hodgkin lymphoma of B-cell type, a median of 23.8 months (range, 13 to 35 months) after starting antiretroviral treatment. Using the method of Kaplan and Meier, the estimated probability of developing lymphoma by 30 months of therapy was 28.6% (CI, 13.7% to 50.3%) and by 36 months, 46.4% (CI, 19.6% to 75.5%). The patients who developed lymphoma had less than 100 T4 cells/mm3 for a median of 17.8 months (range, 7 to 35 months) and less than 50 T4 cells/mm3 for a median of 15.3 months (range, 5.5 to 35 months) before the diagnosis. All patients presented with non-Hodgkin lymphoma in extranodal sites, and two developed primary brain involvement in the setting of Toxoplasma infection. CONCLUSION: Patients with symptomatic HIV infection who survive for up to 3 years on antiretroviral therapy may have a relatively high probability of developing non-Hodgkin lymphoma. Prolonged survival in the setting of profound immunosuppression with substantial T4-cell depletion is probably an important factor in the development of these lymphomas. However, a direct role of therapy itself cannot be totally discounted. As improved therapies for the treatment of HIV infection and its complications result in prolonged survival, non-Hodgkin lymphoma may become an increasingly significant problem.

AIDS-Related Complex↗
PubMed1990

Subcutaneous recombinant granulocyte-macrophage colony-stimulating factor used as a single agent and in an alternating regimen with azidothymidine in leukopenic patients with severe human immunodeficiency virus infection.

We investigated the effects of recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) administered by the subcutaneous route, first alone and then alternating with azidothymidine (AZT), in leukopenic patients with severe human immunodeficiency virus (HIV) infection. Ten patients with acquired immunodeficiency syndrome (AIDS) or related disorders, five of whom could not tolerate conventional doses of AZT, were administered rGM-CSF subcutaneously for 12 days. They then were administered an alternating regimen using AZT for 1 week, followed by 5 days of subcutaneous rGM-CSF and 2 days without any medication. During the initial 12 days of GM-CSF administration, there was an increase in the mean white blood cell (WBC) value. In addition, rGM-CSF stimulated circulating monocytes as evidenced by an increase in superoxide anion production and expression of surface HLA-DR antigen. However, at the same time rGM-CSF increased the serum HIV p24 antigen in each of the six evaluable patients from 189 x/divided by 2.02 pg/mL (geometric mean x/divided by SEM) at entry to 375 x/divided by 2.11 pg/mL (P less than .05). During the subsequent period of alternating AZT and rGM-CSF treatment, serum HIV p24 antigen fell below the day 14 value in most patients, particularly after the weeks of AZT administration. The mean T4 cell value increased in patients who had not previously received AZT, but generally did not change in those who had prior AZT exposure. Hematologic toxicity appeared to be somewhat reduced compared with continuous full-dose AZT therapy, and two patients with previous AZT hematologic toxicity tolerated this alternating regimen for 25 weeks. Additional regimens simultaneously combining these two agents are worth exploring.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Pharmacodynamics of 2',3'-dideoxycytidine: an inhibitor of human immunodeficiency virus.

The incidence of acquired immunodeficiency syndrome and the number of people infected with the human immunodeficiency virus (HIV) is likely to increase into the 1990s and perhaps beyond. Zidovudine, a 2',3'-dideoxynucleoside approved for the treatment of acquired immunodeficiency syndrome, provides immunologic, virologic, and survival benefits. However, because its hematologic toxicity can be dose-limiting, investigations are ongoing with other 2',3'-dideoxynucleosides. After zidovudine, the first of these agents to be tested was 2',3'-dideoxycytidine (ddC), the most potent inhibitor of HIV reverse transcriptase among the dideoxynucleosides tested thus far. Concentrations of ddC as low as 0.5 microM provide protection against HIV in cultured T cells (and monocytes), even at high multiplicities of infection. Like the other dideoxynucleosides, activation of ddC is dependent on intracellular phosphorylation to its 5'-triphosphate form. Efforts are under way to alter enzymatically the intracellular ratio of ddC-5'-triphosphate to deoxycytidine-5'-triphosphate, its endogenous counterpart. ddC has relatively straightforward pharmacokinetics; it has a plasma half-life of about 1.2 hours and an oral bioavailability of about 87 percent. Approximately 75 percent of the drug is excreted unchanged in the urine. Patients treated with ddC have experienced both immunologic and virologic benefit, although long-term high doses are limited by the development of painful peripheral neuropathy. Significant hematologic toxicity is not evident in most patients; low-dose regimens of ddC alone, as well as alternating or in combination with zidovudine, are being tested in an effort to retain antiviral activity while minimizing treatment toxicities.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Dideoxycytidine: current clinical experience and future prospects. A summary.

The reverse transcriptase inhibitor 2',3'-dideoxycytidine (ddC) is capable of mediating virologic and immunologic improvements in some patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. However, severe peripheral neuropathy often develops as a dose-limiting toxicity in ddC-treated patients. Lower doses of ddC may avoid this side effect, while retaining antiviral activity associated with this drug. A series of clinical trials is currently examining regimens employing simultaneous or alternating administration of ddC and 3'-azido-3'-deoxythymidine (zidovudine). Concurrent therapy with more than one drug may allow the use of decreased drug doses and thus reduce dose-dependent toxicities, whereas alternating schedules would provide rest periods from each drug without interrupting therapy. Since zidovudine and ddC possess different toxicity profiles and zidovudine-resistant strains remain susceptible to ddC in vitro, such regimens could theoretically provide additional benefits and reduced toxicity, compared with either agent administered alone. It is hoped that these ongoing and future studies will uncover new and better ways to exploit the therapeutic potential of ddC. However, at present, ddC is an experimental drug and should not be used outside the setting of an approved clinical protocol.

Drug Administration Schedule↗