UMLS:C0019693 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0019693 (HIV)
170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Efavirenz (EFV, Sustiva, Stocrin, DMP-266, L-743,726) is a potent and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase. Pharmacokinetics of EFV was studied in rats and monkeys, the safety assessment species. In rats, after 2 and 5 mg/kg i.v. administrations, the mean CLp, Vdss, and T1/2 were 67 ml/min/kg, 5.0 liters/kg, and 1 h, respectively. EFV was metabolized completely, and the products were excreted almost exclusively via bile. At the higher dose of 15 mg/kg, the CLp was reduced by 36%, implying saturation of metabolism processes. A similar phenomenon occurred in monkeys, where the CLp declined by 60% as the i.v. dose was increased from 5 to 15 mg/kg. After oral dosing, the bioavailability of EFV in rats (10 mg/kg) and monkeys (2 mg/kg) was 16% and 42%, respectively. Higher doses in both species led to disproportionate increases in the AUC and higher Tmax values, suggesting saturation of metabolism and/or prolongation of absorption. The delay in Tmax was more pronounced in monkeys where the plasma concentrations reached plateaus and were sustained for 4 to 20 h. In rats, the prolongation of absorption was due to delayed gastric emptying as demonstrated by >10-fold slower transit of [14C]polyethylene glycol through the stomach of EFV-pretreated animals. The delayed gastric emptying in monkeys also was observed when the animals dosed at 160 mg/kg exhibited emesis, 8 h postdose, which was found to contain a substantial portion of the dose. These results demonstrated that in rats and monkeys, both delayed gastric emptying and saturation of metabolic processes played significant roles in the nonlinear pharmacokinetics of EFV.
...
PMID:Nonlinear pharmacokinetics of efavirenz (DMP-266), a potent HIV-1 reverse transcriptase inhibitor, in rats and monkeys. 988 7

The rapid/high and slow/low phenotypic variants of primary HIV-1 isolates can be distinguished by their differential co-receptor utilization and their ability to productively infect established cell lines. To reveal possible differences in Tat-mediated transactivation, the potential for primary isolate Tat proteins to transactivate the LTR from the laboratory strain HIVLAV/Lai-1 was examined. Using either cell-mediated or PEG-induced fusion of cells infected with primary HIV-1 isolates and HeLaT4LTRbeta-gal cells, it was clear that the Tat protein encoded by all patient isolates efficiently activated transcription from the HIVLAV/Lai-1 LTR. However, infection of HeLaT4LTRbeta-gal cells by primary HIV-1 isolates was transient, suggesting the development of a postpenetration host control of HIV-1 replication at the level of tat activation, a feature not observed for the laboratory-adapted strain HIVIIIB. Although plasmid vectors based on the HIVLAV/Lai-1 LTR remain useful for the development of susceptible established cell lines for titrating primary HIV-1 isolates, the efficacy of such a system would depend upon the stability/duration of Tat activation.
...
PMID:Transient Tat activation of the HIVLAV/Lai-1 LTR by primary HIV-1 phenotypic variants in HeLaT4LTRbeta-gal cells. 1033 53

Heat treatment of normal sera to 56 degrees C for 30 min, a common procedure for the inactivation of viruses, e.g. HIV, reveals the presence of antibodies to neutrophil cytoplasm antigens (ANCA), as detected by indirect immunofluorescence on ethanol-fixed human neutrophils and by antigen-specific ELISA for BPI. Reactivity was not seen to the other common vasculitis-associated antigens proteinase 3 (PR3) or myeloperoxidase (MPO). The effect of temperature was maximal at 56 degrees C, with substantial antibody demonstrable after only 5 min at this temperature. In experiments using polyethylene glycol (PEG)6000 to remove immune complexes, the effect of heating could be abrogated by preincubation with 8% PEG, which suggested that these anti BPI antibodies might be complexed in sera. After passage of normal plasma over a protein G column, the acid-eluted fraction contained elevated levels of antibodies to BPI but not to other vasculitis-associated antigens such as PR3 or MPO, nor to glomerular basement membrane (GBM), the Goodpasture antigen which is recognized by the pathogenically important human antibodies shown to mediate nephritis in transfer experiments. Moreover the levels of anti-BPI in the IgG fraction could be augmented by preincubation with glycine pH 2.5 for 30 min. This anti-BPI activity could be inhibited by addition of the unbound material from the protein G column and this inhibitory material was not heat-labile at 56 degrees C. The molecular specificity of this autoreactivity was confirmed using recombinant BPI in coincubation experiments and the epitope localized to the C or N terminal moieties by the use of recombinant fusion proteins.
...
PMID:Heat treatment of normal human sera reveals antibodies to bactericidal permeability-inducing protein (BPI). 1040 34

A method and approach are described to differentiate classic autoimmune thrombocytopenia (ATP) from immune complex-associated thrombocytopenia in systemic lupus (SLE), hepatitis/chronic liver disease (LIV-ITP) and HIV-1 related thrombocytopenia (HIV-1-ITP). The platelet immunologic profile of IgG, C3C4 and IgM was measured with a solid-phase ELISA, employing 125I-staphylococcal protein A to detect indicator antibody binding. Polyethylene glycol was employed to precipitate immune complexes (PEG-IC). Platelet-associated IgG (PAIgG) was 2.8-, 5.6- and 5.8-fold higher in SLE, LIV-ITP and HIV-1-ITP patients respectively compared to ATP patients: platelet C3C4 was 3.2-, 4.8- and 4.5-fold higher respectively; platelet IgM was 2.2-, 3.7- and 3.8-fold higher respectively; serum PEG-IC levels were 4.2-, 4.8- and 2.1-fold higher respectively. With all parameters measured, there was no overlap between the 75th percentile for ATP patients and the 25th percentile for all three cohorts. The likelihood of having a platelet C3C4 level higher than the highest ATP level was 69% for SLE, 90% for LIV-ITP and 94% for HIV-1-ITP respectively; with PEG-IC measurements the likelihood was 83%, 100% and 100% respectively. Serum IgG, C3, C4, IgM and PEG-IC were examined for a possible relationship with platelet measurements. Except for a positive correlation between serum and platelet IgM in ATP, r = 0.5, P < 0.04, there was no positive correlation with any of the parameters measured. An inverse correlation was noted between PEG-IC level and platelet C3C4 in SLE, r = 0.7, P < 0.04. Thus platelet immunologic profile and serum PEG-IC level measurements differentiated classic ATP from immune complex-associated thrombocytopenias (SLE, LIV-ITP, HIV-1-ITP). Except for IgM measurements in ATP, platelet measurements could not be attributed to their respective serum concentration.
...
PMID:Differentiation of autoimmune thrombocytopenia from thrombocytopenia associated with immune complex disease: systemic lupus erythematosus, hepatitis-cirrhosis, and HIV-1 infection by platelet and serum immunological measurements. 1055 25

The ability of liposomes bearing anti-HLA-DR Fab' fragments at the end termini of polyethyleneglycol chains (sterically stabilized immunoliposomes) to target HLA-DR expressing cells and increase the accumulation of liposomes into lymphoid organs has been evaluated and compared to that of conventional liposomes, sterically stabilized liposomes and conventional immunoliposomes after a single subcutaneous injection to mice. The accumulation of sterically stabilized liposomes in lymph nodes was higher than that of conventional liposomes. Sterically stabilized immunoliposomes accumulated much better than conventional immunoliposomes in all tissues indicating that the presence of PEG has an important effect on the uptake of immunoliposomes by the lymphatic system. Fluorescence microscopy studies showed that sterically stabilized liposomes are mainly localized in macrophage-rich areas such as the subcapsular region of lymph nodes and in the red pulp and marginal zone of the spleen. In contrast, sterically stabilized immunoliposomes mostly accumulated in the cortex in which follicles are located and in the white pulp of the spleen. As the human HLA-DR determinant of the major histocompatibility complex class II is expressed on activated CD4+ T lymphocytes and antigen presenting cells such as monocyte/macrophages and dendritic cells, known as the cellular reservoirs of HIV-1, liposomes bearing anti-HLA-DR antibodies constitute an attractive approach to concentrate drugs in HIV-1 reservoirs and improve their therapeutic effect.
...
PMID:Sterically stabilized liposomes bearing anti-HLA-DR antibodies for targeting the primary cellular reservoirs of HIV-1. 1101 61

Mucosal sites have an innate defense system--which includes immune cells, antibodies, and mucus--to protect the body from opportunistic pathogens. Some sexually transmitted diseases (STDs), such as HIV, utilize host defense mechanisms to evade detection by infecting motile immune cells present at the site. The infected cells migrate through the mucus layer and penetrate the epithelium undetected. A new strategy for preventing STDs could involve inhibiting cell migration through the mucus. One method for inhibiting migration is to alter the barrier property of mucus by modifying its gel structure. Mucin, the structural component of mucus, is a high molecular weight anionic molecule, which forms an entangled fiber network through non-covalent interactions. The addition of nonionic or cationic polymers, such as poly(ethylene glycol) (PEG) or poly(vinyl pyridine) (PVP), altered the overall gel structure as revealed by scanning electron microscopy (SEM), while anionic poly(acrylic acid) had little effect on the structure. Acid residues on mucin associate with PEG through hydrogen bonds to form regions of coalesced fibers within the mucus. PVP, however, interacts with mucin via electrostatic bonds, forming a gel that had areas of aggregated fibers adjacent to regions with virtually no fibers. These results suggest that addition of small amounts of certain synthetic polymers will modify mucus structure; these changes should alter the barrier properties of mucus.
...
PMID:Synthetic polymers alter the structure of cervical mucus. 1121 55

We evaluated the anti-HIV-1 activity of the T-cell-specific protein inhibitor PEG-asparaginase (PEG-ASNase) in human HIV-1-infected T-cells. We further examined the drug synergism between PEG-ASNase and the protease inhibitor Saquinavir (SAQ), both alone and in combination with nucleoside analog reverse transcriptase inhibitors (NRTI). Our drug synergism studies served as a model for an HIV-induced T-cell lymphoma. Phytohemagglutinin [PHA(+)] stimulated T-cells were infected with HIV-1 and then treated with one or more drugs 90 minutes from the viral exposure. To measure inhibition of viral replication, we examined HIV-1 RT and HIV-1 RNA in the supernatant and intracellularly on day 7 post-infection and drug treatment. Last, we examined the effect of administering drugs immediately after HIV-1 infection of T-cells to simulate treatment after an accidental exposure to the virus. PEG-ASNase, even when used alone, has anti-HIV-1 activity in PHA(+)-stimulated T-cells due to inhibition of protein synthesis. When the drug was used with SAQ, the combination was synergistic in inhibiting HIV-1 RT and RNA in the supernatant and intracellularly by 2.5 log10 in comparison with controls. PEG-ASNase and SAQ were even more effective in inhibiting HIV-1 replication when combined with the NRTI inhibitors azidothymidine (AZT) and (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine). The addition of ribonucleotide reductase inhibitor, 2-methyl-1H-isoindole-1,3-dione (MISID), further potentiated the antiviral effect of the regimen. HIV-1 RT and RNA analyses showed that the administration of the PEG-ASNase + SAQ drug combination immediately following exposure to HIV-1 completely inhibited the infection of T-cells in our in vitro T-cell model. From these results we conclude that PEG-ASNase is a valuable T-cell-specific protein inhibitor against HIV-1 infection, when used singly or in combination with a protease inhibitor, an RT inhibitor and an RR inhibitor. Since PEG-ASNase is a drug of choice for the treatment of T-cell lymphomas, a combination regimen containing PEG-ASNase could be very effective in the treatment of HIV-1-induced T-cell lymphoma and possibly AIDS. Future studies are needed in HIV-infected and/or HIV-induced T-cell lymphoma patients to investigate these findings.
...
PMID:Synergistic antiviral effect of PEG-asparaginase (ONCASPAR), with protease inhibitor alone and in combination with RT inhibitors against HIV-1 infected T-cells: a model of HIV-1-induced T-cell lymphoma. 1128 17

Interleukin-2 (IL-2) is a cytokine that induces the proliferation and cytotoxic activation of CD8+ antigen-specific T cells and natural killer (NK) cells, stimulating the clearance of viral-infected and tumor cells. It has a stimulatory effect upon cell-mediated immunity; therefore, reduced IL-2 production may underlie the loss of immune responses in AIDS. These properties make it a desirable therapeutic agent. Clinical trials using IL-2 for the treatment of cancer found that it helped diminish certain types of tumors, but its side effects included capillary leak syndrome, hypotension, fever, and rash. Reduction of these detrimental effects via low doses or intermittent administration of IL-2 has been aided by construction of the hybrid IL-2/polyethylene glycol (PEG) molecule. This has a longer half-life in vivo than IL-2 alone, thus facilitating low dose administration. One potential drawback of IL-2 therapy is that it can stimulate HIV viral production; it is imperative to co-administer an anti-viral agent with IL-2 to offset this effect. A recent study of PEG/IL-2 and AZT yielded evidence of increased CD4+ counts, CD8+ activity, and NK activity. There was no indication of accelerated HIV production. Similar results were obtained in an earlier study. Thus, the use of IL-2 is encouraged as a co-treatment to slow the progression of HIV or as a treatment for HIV-related opportunistic infections.
...
PMID:Interleukin-2. 1136

To achieve an efficient intracellular drug and DNA delivery, attempts were made to target microparticulate drug carriers into cytoplasm bypassing the endocytotic pathway. TAT peptides derived from the HIV-1 TAT protein facilitate intracellular delivery of proteins and small colloidal particles. We demonstrated that relatively large drug carriers, such as 200-nm liposomes, can also be delivered into cells by TAT peptide attached to the liposome surface. Liposomes were fluorescently labeled with membranotropic rhodamine-phosphatidylethanolamine or by entrapping FITC-dextran. Incubation of fluorescent TAT liposomes with mouse Lewis lung carcinoma cells, human breast tumor BT20 cells, and rat cardiac myocyte H9C2 results in intracellular localization of certain liposomes. Steric hindrances for TAT peptide x cell interaction (attachment of TAT directly to the liposome surface without spacer or the presence of a high MW polyethylene glycol on the liposome surface) abolish liposome internalization, evidencing the importance of direct contact of TAT peptide with the cell surface. Low temperature or metabolic inhibitors, sodium azide or iodoacetamide, have little influence on the translocation of TAT liposomes into cells, confirming the energy-independent character of this process. The approach may have important implications for drug delivery directly into cell cytoplasm.
...
PMID:TAT peptide on the surface of liposomes affords their efficient intracellular delivery even at low temperature and in the presence of metabolic inhibitors. 1143 7

We report an efficient solid-phase synthesis of C-terminal tyrosine peptide aldehydes based on the HIV protease inhibitors (S)-MAPI and GE 20372 A. Our strategy consisted of anchoring the side chain of Dde-Tyrosinol (5) onto the brominated Wang linker derivative ((4-bromomethyl)-phenoxy-allyl acetate) (6) to give after ester hydrolysis the N(alpha)-(Dde)-O-(4-methylphenoxyacetic acid)-L-Tyrosinol template (8). This was attached to aminomethyl resin and elongated using standard Fmoc protocols. Importantly there was no evidence of esterification side reactions. The unsymmetrically substituted urea linkage of the (S)-MAPI family was incorporated using the N(alpha)-(4-nitrophenyloxycarbonyl)amino acid tert-butyl esters following which the protected tetrapeptide alcohol immobilized on the solid support was oxidized to its corresponding aldehyde using sulfur trioxide-pyridine. The efficiency and reliability of the oxidation step was dramatically improved by the incorporation of a small PEG-spacer between the linker and the solid support. The tetrapeptides 12a and 12b were cleaved by acidolysis, purified by RP HPLC, and isolated in high yield and purity, demonstrating the success of the whole synthetic process.
...
PMID:Solid-Phase Synthesis of Tyrosine Peptide Aldehydes. Analogues of (S)-MAPI. 1167 48

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>