scholarly journals Different effect of benzylacyclouridine on the toxic and therapeutic effects of azidothymidine in mice

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2216-2221 ◽  
Author(s):  
A Falcone ◽  
JW Darnowski ◽  
RM Ruprecht ◽  
SH Chu ◽  
I Brunetti ◽  
...  
Keyword(s):  
Leukemia Virus ◽  
Hematologic Toxicity ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Aids Related Complex ◽  
Effective Doses ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome ◽  
Oral Doses

Abstract It has been reported that in vitro uridine (Urd) can reverse azidothymidine (AZT) cytotoxicity without decreasing anti-human immunodeficiency virus (HIV) activity. Our studies in mice have shown that daily oral doses of benzylacyclouridine (BAU), an inhibitor of Urd breakdown, also reduces AZT hematologic toxicity, presumably by elevating the plasma concentration of Urd. We now extend these murine studies and report the effect of various doses of exogenous Urd, various doses of BAU, or the combination of BAU and Urd, administered daily, on AZT-induced toxicity. In mice receiving concomitant AZT, daily doses of Urd of 1,000 to 2,000 mg/kg increase peripheral reticulocytes and slightly reduce AZT-induced hematologic toxicity. However, the range of effective doses is narrow, and higher doses of Urd (greater than 3,000 mg/kg/d) significantly enhance hematologic toxicity. At its most effective dose, (2,000 mg/kg/d), Urd produces 28% mortality. In contrast, BAU doses up to 300 mg/kg/d reduced AZT-related hematologic toxicity in a dose-dependent manner without mortality. Higher daily doses of BAU and the combination of BAU with low doses of Urd were not more effective. Studies conducted in mice infected with the Rauscher murine leukemia virus (RLV) indicate that BAU does not impair the antiretroviral effect of AZT when administered at doses that reduce AZT-induced anemia and leukopenia. These findings may be significant for the treatment of patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex.

scholarly journals Different effect of benzylacyclouridine on the toxic and therapeutic effects of azidothymidine in mice

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2216-2221
Author(s):  
A Falcone ◽  
JW Darnowski ◽  
RM Ruprecht ◽  
SH Chu ◽  
I Brunetti ◽  
...  
Keyword(s):  
Leukemia Virus ◽  
Hematologic Toxicity ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Aids Related Complex ◽  
Effective Doses ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome ◽  
Oral Doses

It has been reported that in vitro uridine (Urd) can reverse azidothymidine (AZT) cytotoxicity without decreasing anti-human immunodeficiency virus (HIV) activity. Our studies in mice have shown that daily oral doses of benzylacyclouridine (BAU), an inhibitor of Urd breakdown, also reduces AZT hematologic toxicity, presumably by elevating the plasma concentration of Urd. We now extend these murine studies and report the effect of various doses of exogenous Urd, various doses of BAU, or the combination of BAU and Urd, administered daily, on AZT-induced toxicity. In mice receiving concomitant AZT, daily doses of Urd of 1,000 to 2,000 mg/kg increase peripheral reticulocytes and slightly reduce AZT-induced hematologic toxicity. However, the range of effective doses is narrow, and higher doses of Urd (greater than 3,000 mg/kg/d) significantly enhance hematologic toxicity. At its most effective dose, (2,000 mg/kg/d), Urd produces 28% mortality. In contrast, BAU doses up to 300 mg/kg/d reduced AZT-related hematologic toxicity in a dose-dependent manner without mortality. Higher daily doses of BAU and the combination of BAU with low doses of Urd were not more effective. Studies conducted in mice infected with the Rauscher murine leukemia virus (RLV) indicate that BAU does not impair the antiretroviral effect of AZT when administered at doses that reduce AZT-induced anemia and leukopenia. These findings may be significant for the treatment of patients with acquired immunodeficiency syndrome (AIDS) and AIDS-related complex.

scholarly journals A phase 1 study of adoptive transfer of autologous CD8+ T lymphocytes in patients with acquired immunodeficiency syndrome (AIDS)-related complex or AIDS

Blood ◽  
1993 ◽  
Vol 81 (8) ◽  
pp. 2093-2101 ◽  
Author(s):  
M Ho ◽  
J Armstrong ◽  
D McMahon ◽  
G Pazin ◽  
XL Huang ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Acquired Immunodeficiency Syndrome ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Cd8 Cells ◽  
Cd8 T Lymphocytes ◽  
Aids Related Complex ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome

Based on preclinical studies showing that CD8+ T lymphocytes of human immunodeficiency syndrome (HIV)-infected subjects have anti-HIV activities, a phase 1 study was undertaken to determine the safety and feasibility of infusing in vitro purified, activated, and expanded CD8+ cells as a therapeutic measure in seven patients with acquired immunodeficiency syndrome (AIDS)-related complex (ARC) or AIDS. Autologous CD8+ cells were first selectively isolated in monoclonal antibody-coated flasks from peripheral blood mononuclear cells recovered by leukapheresis. They were then cultured and expanded with phytohemagglutinin and recombinant interleukin-2 (rIL-2) before infusion. Five cycles of isolations and infusions of increasing numbers of CD8+ T cells were achieved in five of seven subjects. Five cycles could not be completed in two subjects with AIDS whose CD4+ cell counts were < or = 48/microliters. Infusions of CD8+ cells alone were well tolerated. Four patients received rIL-2 by continuous infusion for 5 days with their final cycle of CD8+ cells. All developed reversible adverse effects attributable to rIL-2. After infusion, 111In-labeled CD8+ cells quickly accumulated in the lungs, with less than 10% of the labeled cells remaining in the circulation. After 24 hours, labeled CD8+ cells were reduced in the lungs, but increased and persisted in liver, spleen, and bone marrow. Four of five patients who were treated with multiple infusions of CD8+ cells have improved or remained clinically stable, and the fifth developed Pneumocystis carinii pneumonia but recovered. This study demonstrated that infusion of autologous, in vitro expanded and activated CD8+ cells was feasible and clinically well tolerated in five of seven subjects with advanced HIV infections.

scholarly journals A phase 1 study of adoptive transfer of autologous CD8+ T lymphocytes in patients with acquired immunodeficiency syndrome (AIDS)-related complex or AIDS

Blood ◽  
1993 ◽  
Vol 81 (8) ◽  
pp. 2093-2101 ◽  
Author(s):  
M Ho ◽  
J Armstrong ◽  
D McMahon ◽  
G Pazin ◽  
XL Huang ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Acquired Immunodeficiency Syndrome ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Cd8 Cells ◽  
Cd8 T Lymphocytes ◽  
Aids Related Complex ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome

Abstract Based on preclinical studies showing that CD8+ T lymphocytes of human immunodeficiency syndrome (HIV)-infected subjects have anti-HIV activities, a phase 1 study was undertaken to determine the safety and feasibility of infusing in vitro purified, activated, and expanded CD8+ cells as a therapeutic measure in seven patients with acquired immunodeficiency syndrome (AIDS)-related complex (ARC) or AIDS. Autologous CD8+ cells were first selectively isolated in monoclonal antibody-coated flasks from peripheral blood mononuclear cells recovered by leukapheresis. They were then cultured and expanded with phytohemagglutinin and recombinant interleukin-2 (rIL-2) before infusion. Five cycles of isolations and infusions of increasing numbers of CD8+ T cells were achieved in five of seven subjects. Five cycles could not be completed in two subjects with AIDS whose CD4+ cell counts were < or = 48/microliters. Infusions of CD8+ cells alone were well tolerated. Four patients received rIL-2 by continuous infusion for 5 days with their final cycle of CD8+ cells. All developed reversible adverse effects attributable to rIL-2. After infusion, 111In-labeled CD8+ cells quickly accumulated in the lungs, with less than 10% of the labeled cells remaining in the circulation. After 24 hours, labeled CD8+ cells were reduced in the lungs, but increased and persisted in liver, spleen, and bone marrow. Four of five patients who were treated with multiple infusions of CD8+ cells have improved or remained clinically stable, and the fifth developed Pneumocystis carinii pneumonia but recovered. This study demonstrated that infusion of autologous, in vitro expanded and activated CD8+ cells was feasible and clinically well tolerated in five of seven subjects with advanced HIV infections.

scholarly journals Mechanisms underlying the antifibrotic properties of noninhibitory PAI-1 (PAI-1R) in experimental nephritis

2009 ◽  
Vol 297 (4) ◽  
pp. F1045-F1054 ◽  
Author(s):  
Yufeng Huang ◽  
Wayne A. Border ◽  
Daniel A. Lawrence ◽  
Nancy A. Noble
Keyword(s):  
Half Life ◽  
Stable Form ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Therapeutic Action ◽  
Protease Inhibition ◽  
Ecm Degradation ◽  
Dose Dependent ◽  
Pai 1

Administration of a mutant, noninhibitory PAI-1 (PAI-1R), reduces disease in experimental glomerulonephritis. Here we investigated the importance of vitronectin (Vn) binding, PAI-1 stability and protease binding in this therapeutic effect using a panel of PAI-1 mutants differing in half-life, protease binding, and Vn binding. PAI-1R binds Vn normally but does not inhibit proteases. PAI-1AK has a complete defect in Vn binding but retains full inhibitory activity, with a short half-life similar to wild-type (wt)-PAI-1. Mutant 14-lb is identical to wt-PAI-1 but with a longer half-life. PAI-1K has defective Vn binding, inhibits proteases normally, and has a long half-life. In vitro wt-PAI-1 dramatically inhibited degradation of mesangial cell ECM while the AK mutant had much less effect. Mutants 14-1b and PAI-1K, like wt-PAI-1, inhibited matrix degradation but PAI-1R failed to reverse this inhibition although PAI-1R reversed the wt-PAI-1-induced inhibition of ECM degradation in a plasmin-, time-, and dose-dependent manner. Thus the ability of PAI-1 to inhibit ECM degradation is dependent both on its antiproteinase activity and on maintaining an active conformation achieved either by Vn binding or mutation to a stable form. Administration of these PAI-1 mutants to nephritic rats confirmed the in vitro data; only PAI-1R showed therapeutic effects. PAI-1K did not bind to nephritic kidney, indicating that Vn binding is essential to the therapeutic action of PAI-1R. The ability of PAI-1R to remain bound to Vn even in a high-protease environment is very likely the key to its therapeutic efficacy. Furthermore, because both PAI-1R and 14-1b bound to the nephritic kidney in the same pattern and differ only in their ability to bind proteases, lack of protease inhibition is also keyed to PAI-1R's therapeutic action.

scholarly journals Tolerogenic Splenic IDO+Dendritic Cells from the Mice Treated with Induced-Treg Cells Suppress Collagen-Induced Arthritis

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Jie Yang ◽  
Yiming Yang ◽  
Huahua Fan ◽  
Hejian Zou
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Foxp3 Expression ◽  
Treated Group ◽  
Treg Cells ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Collagen Induced Arthritis

TGF-β-induced regulatory T cells (iTregs) retain Foxp3 expression and immune-suppressive activity in collagen-induced arthritis (CIA). However, the mechanisms whereby transferred iTregs suppress immune responses, particularly the interplay between iTregs and dendritic cells (DCs)in vivo, remain incompletely understood. In this study, we found that after treatment with iTregs, splenic CD11c+DCs, termed “DCiTreg,” expressed tolerogenic phenotypes, secreted high levels of IL-10, TGF-β, and IDO, and showed potent immunosuppressive activityin vitro. After reinfusion with DCiTreg, marked antiarthritic activity improved clinical scores and histological end-points were observed. The serological levels of inflammatory cytokines and anti-CII antibodies were low and TGF-βproduction was high in the DCiTreg-treated group. DCiTregalso induced new iTregsin vivo. Moreover, the inhibitory activity of DCiTregon CIA was lost following pretreatment with the inhibitor of indoleamine 2,3-dioxygenase (IDO). Collectively, these findings suggest that transferred iTregs could induce tolerogenic characteristics in splenic DCs and these cells could effectively dampen CIA in an IDO-dependent manner. Thus, the potential therapeutic effects of iTregs in CIA are likely maintained through the generation of tolerogenic DCsin vivo.

scholarly journals Lack of evidence of prolonged human immunodeficiency virus infection before antibody seroconversion

Blood ◽  
1988 ◽  
Vol 71 (6) ◽  
pp. 1752-1754
Author(s):  
JE Groopman ◽  
T Caiazzo ◽  
MA Thomas ◽  
RA Ferriani ◽  
S Saltzman ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
High Risk ◽  
Screening Tests ◽  
Homosexual Men ◽  
Immunodeficiency Virus ◽  
Aids Related Complex ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome ◽  
Very High ◽  
Considerable Concern

Recently, considerable concern has been raised regarding the possibility that antibody-based screening tests for the human immunodeficiency virus (HIV) may fail to detect certain high-risk individuals for prolonged periods of time. It has been proposed that testing for HIV-related antigen may be a necessary procedure to detect such individuals. To address this issue, we longitudinally studied two groups of homosexual men: direct sexual partners of acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) patients and individuals who ultimately sero-converted. There was no evidence of prolonged infection with HIV in the absence of detectable antibody in these two groups. It appears at this time that, even among subjects at very high risk for HIV infection, currently available antibody-based assays are sufficient to identify infected individuals.

scholarly journals Induction of PI3K/Akt-Mediated Apoptosis in Osteoclasts Is a Key Approach for Buxue Tongluo Pills to Treat Osteonecrosis of the Femoral Head

2021 ◽  
Vol 12 ◽  
Author(s):  
Dan Wang ◽  
Yicheng Liu ◽  
Dandan Tang ◽  
Shujun Wei ◽  
Jiayi Sun ◽  
...  
Keyword(s):  
Femoral Head ◽  
Functional Annotation ◽  
Caspase 3 ◽  
Differentially Expressed Gene ◽  
Pathway Enrichment Analysis ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Clinical Practices ◽  
Key Genes

The Buxue Tongluo pill (BTP) is a self-made pill with the functions of nourishing blood, promoting blood circulation, dredging collaterals, and relieving pain. It consists of Angelica sinensis (Oliv.) Diels, Pheretima aspergillum (E.Perrier), Panax notoginseng (Burk.) F. H. Chen, Astragalus membranaceus (Fisch.) Bge, and Glycyrrhiza uralensis Fisch. Various clinical practices have confirmed the therapeutic effect of BTP on osteonecrosis of the femoral head (ONFH), but little attention has been paid to the study of its bioactive ingredients and related mechanisms of action. In this study, UPLC/MS-MS combined with GEO data mining was used to construct a bioactive ingredient library of BTP and a differentially expressed gene (DEG) library for ONFH. Subsequently, Cytoscape (3.7.2) software was used to analyze the protein–protein interaction between BTP and DEGs of ONFH to screen the key targets, and functional annotation analysis and pathway enrichment analysis were carried out. Finally, 34 bioactive compounds were screened, which acted on 1,232 targets. A total of 178 DEGs were collected, and 17 key genes were obtained after two screenings. By bioinformatics annotation on these key genes, a total of 354 gene ontology (GO) functional annotation analyses and 42 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were obtained. The present study found that GO and KEGG enrichment were mainly related to apoptosis, suggesting that BTP may exert an anti-ONFH effect by promoting osteoclast apoptosis. Experiments in vitro demonstrated that BTP could increase the mitochondrial membrane potential (MMP) and induce remarkable apoptosis in osteoclasts. Furthermore, we determined the apoptosis marker of cleaved(C)-caspase-3, bcl-2, and bax and found that BTP could upregulate the C-caspase-3 and bax expression in osteoclasts and decrease the expression of bcl-2, p-Akt, and p-PI3K in a dose-dependent manner, indicating that BTP could induce PI3K/Akt-mediated apoptosis in osteoclasts to treat ONFH. This study explored the pharmacodynamic basis and mechanism of BTP against ONFH from the perspective of systemic pharmacology, laying a foundation for further elucidating the therapeutic effects of BTP against ONFH.

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