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)

The existence of sanctuary sites for human immunodeficiency virus type 1 (HIV-1) may potentially endanger the efficacy of antiretroviral therapy in the long term and may even make eradication of HIV-1 from the infected body impossible. Potential 'classic' sanctuary sites for HIV-1 are the central nervous system and the testes, but long-lived cell populations (such as macrophages) or latently infected (resting) CD4 cells may also be considered a sanctuary for HIV-1. These potential sanctuary sites, and putative underlying biochemical mechanisms such as the divergent phosphorylation properties of nucleoside reverse transcriptase inhibitors in different cell populations and the affinity of drugs for the multidrug transporter P-glycoprotein, are discussed.
 ...
PMID:Sanctuary sites in HIV-1 infection. 1072 4

HIV protease inhibitors have proven remarkably effective in treating HIV-1 infection. However, some tissues such as the brain and testes (sanctuary sites) are possibly protected from exposure to HIV protease inhibitors due to drug entry being limited by the membrane efflux transporter P-glycoprotein, located in the capillary endothelium. Intravenous administration of the novel and potent P-glycoprotein inhibitor LY-335979 to mice (1-50 mg/kg) increased brain and testes concentration of [(14)C]nelfinavir, up to 37- and 4-fold, respectively, in a dose-dependent fashion. Similar effects in brain levels were also observed with (14)C-labeled amprenavir, indinavir, and saquinavir. Because [(14)C]nelfinavir plasma drug levels were only modestly increased by LY-335979, the increase in brain/plasma and testes/plasma ratios of 14- to 17- and 2- to 5-fold, respectively, was due to increased tissue penetration. Less potent P-glycoprotein inhibitors like valspodar (PSC-833), cyclosporin A, and ketoconazole, as well as quinidine and verapamil, had modest or little effect on brain/plasma ratios but increased plasma nelfinavir concentrations due to inhibition of CYP3A-mediated metabolism. Collectively, these findings provide "proof-of-concept" for increasing HIV protease inhibitor distribution into pharmacologic sanctuary sites by targeted inhibition of P-glycoprotein using selective and potent agents and suggest a new therapeutic strategy to reduce HIV-1 viral replication.
 ...
PMID:Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. 1082 Jan 37

The distribution of currently available anti-HIV drugs into the CNS is reviewed with a focus on transport mechanisms. Among these drugs, nucleoside analogs are most well studied for their CNS distribution. The average reported values of the CSF/plasma steady-state concentration or corresponding AUC ratios are 0.23 (AZT), 0.06 (ddI), 0.04 (ddC), 0.49 (d4T), and 0.08 (3TC). Active efflux transport out of the CNS appears to be a predominant mechanism limiting nucleoside access to the CNS, although poor penetration may contribute to some extent for some polar nucleosides. The nature of the efflux pump for these drugs is speculated to be MRP-like transporter(s) in blood-brain and blood-CSF barriers. For non-nucleoside and protease inhibitors, much research remains to be done on the extent, time course, and mechanisms of their CNS distribution. The CNS penetration of some protease inhibitors is restricted by P-glycoprotein. A better understanding of transport mechanisms of anti-HIV drugs in the CNS is essential to develop approaches to enhance CNS delivery of available drugs and to identify new drugs less subject to active efflux transporter(s) in the CNS.
 ...
PMID:Investigation of distribution, transport and uptake of anti-HIV drugs to the central nervous system. 1083 65

Orally administered anti-HIV drugs must be adequately and consistently absorbed for therapy to be successful. This review discusses the barriers to achieving oral bioavailability for the currently available anti-HIV drugs. Most reverse transcriptase inhibitors have good oral bioavailabilities. Didanosine bioavailability could be reduced by acid instability, first-pass hepatic metabolism, and possibly poor intestinal permeation. Bioavailability of zidovudine is also reduced by first-pass metabolism. The non-nucleoside reverse transcriptase inhibitors have oral bioavailabilities most probably limited by poor aqueous solubility. For each of the currently marketed HIV protease inhibitors, solubility, intestinal permeability, and first-pass metabolism could contribute to reducing oral bioavailability. The intestinal permeabilities of these agents is influenced by secretory transport. In vitro, secretory transport, which appears to be P-glycoprotein-mediated, is much greater than permeation in the absorptive direction for indinavir, nelfinavir, ritonavir, and saquinavir. The mechanisms of secretory intestinal transport are reviewed, and the factors that may influence the impact of secretory transport in vivo are considered.
 ...
PMID:P-glycoprotein, secretory transport, and other barriers to the oral delivery of anti-HIV drugs. 1083 70

Two prominent members of the ATP-binding cassette superfamily of transmembrane proteins, multidrug resistance 1 (MDR1) P-glycoprotein and multidrug resistance protein 1 (MRP1), can mediate the cellular extrusion of xenobiotics and (anticancer) drugs from normal and tumor cells. The MRP subfamily consists of at least six members, and here we report the functional characterization of human MRP5. We found resistance against the thiopurine anticancer drugs, 6-mercaptopurine (6-MP) and thioguanine, and the anti-HIV drug 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in MRP5-transfected cells. This resistance is due to an increased extrusion of PMEA and 6-thioinosine monophosphate from the cells that overproduce MRP5. In polarized Madin-Darby canine kidney II (MDCKII) cells transfected with an MRP5 cDNA construct, MRP5 is routed to the basolateral membrane and these cells transport S-(2,4-dinitrophenyl)glutathione and glutathione preferentially toward the basal compartment. Inhibitors of organic anion transport inhibit transport mediated by MRP5. We speculate that MRP5 might play a role in some cases of unexplained resistance to thiopurines in acute lymphoblastic leukemia and/or to antiretroviral nucleoside analogs in HIV-infected patients.
 ...
PMID:Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. 1084 50

Treatment of the human immunodeficiency virus (HIV) is restricted by therapeutic escape. The biological mechanisms of this chemoresistance rely notably on the modulation of cell kinase and P-glycoprotein (P-gp) expression. In this study, we investigated, in cynomolgus macaques, the roles of SHIV89.6P infection and of HAART in the mRNA expression of these cell factors. SHIV infection, or associated pathophysiological disorders, increase both thymidine kinase and thymidylate kinase mRNA expression and decrease those of P-gp. On the other hand, the expression of other cell kinases is not modulated. In parallel, HAART accentuates the decrease of P-gp expression and attenuates the increase of kinase expression. On the whole, such metabolic disorders, evidenced herein an animal model of HIV infection, could be involved in HIV-infected patients.
 ...
PMID:[Evaluation of the effect of early and massive tritherapy on the expression of cellular factors potentially implicated in antiretroviral therapy resistance]. 1094 47

Protease inhibitors are very effective in treating patients infected with HIV. However, many drugs in this class penetrate poorly into the central nervous system (CNS) and may permit this site to be a sanctuary from which resistant virus can emerge. Previous studies have shown that the protease inhibitor saquinavir (SQV) interacts with the multidrug transport system, P-glycoprotein (P-gp), expressed in epithelial cells in the gut mucosa and at the blood-brain barrier, and thus might affect both the oral absorption and the penetration of SQV into the CNS. To determine whether SQV is a substrate for P-gp, its uptake was determined in cancer cells, which do (Dx5) and do not (MES-SA) express P-gp. The distribution of SQV between brain tissue and plasma was also investigated in rats and in normal and P-gp-deficient mdr1a(-/-) mice. The distribution ratio of SQV in plasma:brain:cerebrospinal fluid was approximately 100:10:0.2 in rats. The accumulation of SQV was enhanced in MES-SA cells (P-gp-negative) versus Dx5 cells (P-gp-positive). Bolus i.v. injection of [(14)C]SQV (2 and 5 mg/kg) into mdr1a(-/-) and normal mice (n = 3 or 4) resulted in 3-fold higher radioactivity in brains from mdr1a(-/-) mice. Similarly, oral administration of [(14)C]SQV (500 mg/kg) resulted in a 5-fold increase in systemic exposure and a 10-fold increase in brain levels in mdr1a(-/-) mice. These data demonstrate that saquinavir is a substrate for P-gp and that this transport system may play a role in limiting oral absorption and CNS exposure to this protease inhibitor.
 ...
PMID:The disposition of saquinavir in normal and P-glycoprotein deficient mice, rats, and in cultured cells. 1095 Aug 49

The protease inhibitors are a new class of drugs for the treatment of HIV infection. Results of treatment have proved beneficial to HIV positive patients, resulting in slower disease progression to aids and death. However the potential of drug interactions is high because of the drug-transporting P-glycoprotein and cytochrome P450 3A4-mediated metabolism. Administration of protease inhibitors may result in increased or decreased concentrations of co-administered drugs, and the plasma concentration of protease inhibitors may be affected by other drugs. It is possible to take advantage of the interactions by combining two protease inhibitors. Attention is drawn to the protease inhibitors and their possible interactions because of the advantages and disadvantages this implies. It is possible to monitor interactions by measuring plasma concentrations of the protease inhibitors.
 ...
PMID:[HIV protease inhibitors and interactions]. 1098

A depressed level of natural killer (NK) activity is one of the various immunologic abnormalities in human immunodeficiency virus (HIV) infection. Interleukin-15 (IL-15), an immunotherapeutic candidate in HIV infection, increases NK activity and induces the excretion of CC-chemokines from divergent immune cells, but the mechanisms of NK activity enhancement by IL-15 stimulation is not clearly established in HIV infection. This study examined whether CC-chemokines, which are known to increase NK activity, are secreted adequately in HIV-infected individuals, and also investigated whether P-glycoprotein is involved in NK activity enhancement after IL-15 administration. NK activity increased with IL-15 stimulation in NK cells of HIV-infected individuals, as it does in normal NK cells. IL-15 stimulates NK cells to secrete CC-chemokines, such as, macrophage inflammatory protein-1alpha (MIP-1alpha), macrophage chemotactic protein-1alpha (MCP-1alpha) and regulated upon activation, normal T cells expressed and secreted (RANTES) in both HIV-infected individuals and controls with no significant difference. P-glycoprotein expression and function is decreased in HIV-infected individuals and restored only in NK cells of HIV-infected individuals after IL-15 stimulation. P-glycoprotein may play a role in the mechanism of increased NK cell activity in HIV-infected individuals after IL-15 stimulation.
 ...
PMID:Restoration of P-glycoprotein function is involved in the increase of natural killer activity with exogenous interleukin-15 in human immunodeficiency virus-infected individuals. 1107 20

To identify specific transporters that drive xenobiotics from central nervous system to blood, the accumulation of fluorescent drugs was studied in isolated capillaries from rat and pig brain using confocal microscopy and quantitative image analysis. Luminal accumulation of daunomycin and of fluorescent derivatives of cyclosporine A (CSA) and ivermectin was concentrative, specific, and energy-dependent (inhibition by NaCN). Transport was reduced by PSC 833, ivermectin, verapamil, CSA, and vanadate, but not by leukotriene C(4) (LTC(4)), indicating the involvement of P-glycoprotein. Luminal accumulation of the fluorescent organic anions sulforhodamine 101 and fluorescein methotrexate was also concentrative, specific, and energy-dependent. LTC(4), chlorodinitrobenzene, and vanadate reduced transport of these compounds, but PSC 833 and verapamil did not, indicating the involvement of a multidrug resistance-associated protein (Mrp). Immunostaining localized P-glycoprotein and Mrp2 to the luminal surface of the capillary endothelium and quantitative polymerase chain reaction showed Mrp1 and Mrp2 expression. Finally, the HIV protease inhibitors saquinavir and ritonavir were potent inhibitors of transport mediated by both P-glycoprotein and Mrp. These results validate a new method for studying drug transport in isolated brain capillaries and implicate both P-glycoprotein and one or more members of the Mrp family in drug transport from central nervous system to blood.
 ...
PMID:Xenobiotic transport across isolated brain microvessels studied by confocal microscopy. 1109 74


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