Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DXG ([2R-cis]-2-amino-1,9-dihydro-9-[2-[hydroxymethyl]-1,3-dioxolan-4-yl]-6H-purin-6-one) and its prodrug DAPD ([2R-cis]-4-[2,6-diamino-9H-purin-9-yl]-1,3-dioxolane-2-methanol; amdoxovir) are novel 2',3'-dideoxynucleosides (ddNs) displaying activity against human immunodeficiency virus type 1 (HIV-1). In this paper, we describe the development of an enzymatic assay for determining the intracellular active metabolite of DXG and DAPD, DXG triphosphate (DXGTP), in peripheral blood mononuclear cells (PBMCs) from HIV-infected patients. The assay involves inhibition of HIV reverse transcriptase (RT), which normally incorporates radiolabeled deoxynucleoside triphosphates (dNTPs) into a synthetic template primer. DXGTP (0.6 pmol) inhibited control product formation with or without a preincubation step. Inhibition was greatest when the template primer was most diluted. DAPDTP inhibited control product formation only at very high levels (50 pmol) and when a preincubation procedure was used. However, reduced template primer stability in assays using preincubation steps, coupled with potential interference by DAPDTP, led to the current assay method for DXGTP being performed without preincubation. Standard DXGTP inhibition curves were constructed. The presence of PBMC extracts or endogenous dGTP did not interfere with the DXGTP assay. Intracellular DXGTP and dGTP concentrations were determined in PBMCs from HIV-infected patients receiving oral DAPD (500 mg b.i.d.). Peak concentrations of DXGTP were obtained 8 h after dosing and were measurable through 48 h postdose. Levels of endogenous dGTP were also determined over 48 h. No direct relationship was observed between concentrations of DXGTP and dGTP. Quantification of DXGTP concentrations in PBMCs from patients receiving a clinically relevant dose of DAPD is possible with this enzymatic assay.
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PMID:Enzymatic assay for measurement of intracellular DXG triphosphate concentrations in peripheral blood mononuclear cells from human immunodeficiency virus type 1-infected patients. 1249 99

A sensitive high-performance liquid chromatography method was developed with spectrofluorimetric detection for the determination of tenofovir, a new HIV reverse transcriptase inhibitor, in human plasma. After precipitation of 200 microl of plasma samples by methanol and evaporation of the supernatant, fluorescent derivatized compounds were obtained by a 40-min incubation at 80 degrees C with chloroacetaldehyde 0.34% at pH 4.5. The assay was performed isocratically using 5 mM Na(2)HPO(4) (pH 6), containing tetrabutylammonium (TBA) chloride 5 mM, and acetonitrile (85:15, v/v) as mobile phase, and a Cluzeau C(8) plus satisfaction column maintained at 35 degrees C. Detection was performed at excitation and emission wavelengths set at 236 and 420 nm, respectively. In these conditions, tenofovir can be separated from adefovir, the internal standard, and endogenous substances. The method was found to be linear and has been validated over a concentration range of 5-1000 microg/l. The average coefficient of the limit of quantification (5 microg/l) was 5.38% and at this concentration, a signal-to-noise ratio of 500 was measured
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PMID:Determination of tenofovir in human plasma by high-performance liquid chromatography with spectrofluorimetric detection. 1255 52

HIV protease inhibitors are important antiretroviral drugs which have substantially reduced the morbidity and mortality associated with HIV-1 infection. Recent data have shown relationships between plasma concentrations of the protease inhibitors and clinical response, which makes therapeutic drug monitoring valuable. We have developed and validated an assay, using liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS), for the routine quantification of the six licensed protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir) and the pharmacologically active nelfinavir metabolite M8 in plasma. The sample pretreatment consisted of protein precipitation with a mixture of methanol and acetronitrile using only 100 microl of plasma. Chromatographic separation was performed on an Inertsil ODS3 column (50 x 2.0 mm i.d., particle size 5 microm), with a quick stepwise gradient using an acetate buffer (pH 5) and methanol, at a flow rate of 0.5 ml min(-1). The analytical run time was 5.5 min. The use of a 96-well plate autosampler allowed batch sizes up to 150 patient samples. The triple-quadrupole mass spectrometer was operated in the positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated over the concentration ranges 0.01-10 microg ml(-1) for indinavir and saquinavir, 0.1-10 microg ml(-1) for amprenavir, 0.05-10 microg ml(-1) for nelfinavir and ritonavir, 0.1-20 microg ml(-1) for lopinavir and 0.01-5 microg ml(-1) for M8. Saquinavir-d(5) and indinavir-d(6) were used as internal standards. The coefficients of variation were always <10% for both intra-day and inter-day precisions for each compound. Mean accuracies were also between the designated limits (+/-15%). The validated concentration ranges proved to be adequate in daily practice. This robust and fast LC/MS/MS assay is now successfully applied for routine therapeutic drug monitoring and pharmacokinetic studies in our hospital.
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PMID:Rapid quantification of HIV protease inhibitors in human plasma by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. 1257 82

Phytochemical investigation of the methanol extract of Euchresta formosana resulted in the isolation of thirty-four compounds. Compounds 1, 3-12, 15, 27, 29 and 32-24 were isolated from this species for the first time. These compounds were identified by spectral analyses and tested for antiplatelet aggregation and anti-HIV activities. Among these compounds, tectorigenin (1), 3',4',5-trihydroxyisoflavone (3), and euchretin F (19) were the most effective antiplatelet aggregation compounds; they inhibited both AA- (arachidonic acid) and collagen-induced platelet aggregation. Meanwhile, flemiphyllin (B), quercetin (13), euchretin M (23), and formosanatin C (26) inhibited HIV replication in H9 lymphocyte cells.
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PMID:Antiplatelet and anti-HIV constituents from Euchresta formosana. 1271 20

Seven new sesquiterpenes, named litseagermacrane (1), 7-epi-eudesm-4(15)-ene-1alpha,6alpha-diol (2), 5-epi-eudesm-4(15)-ene-1beta,6beta-diol (4), litseahumulanes A (6) and B (7), and litseachromolaevanes A (11) and B (12), as well as the known compounds 7-epi-eudesm-4(15)-ene-1beta,6beta-diol (3), eudesm-4(15)-ene-1beta,6alpha-diol (5), octahydro-4-hydroxy-3alpha-methyl-7-methylene-alpha-(1-methylethyl)-1H-indene-1-methanol (8), 10-hydroxyl-15-oxo-alpha-cadinol (9), and aphanamol II (10), were isolated from an anti-HIV fraction of the leaves and twigs of Litsea verticillata Hance (Figure 1). Isolates 1, 4, and 12 were found to inhibit HIV-1 replication in a green fluorescent protein (GFP)-based reporter cell line (HOG.R5) with IC(50) values of 6.5 (27.5), 17.4 (73.1), and 28.0 (119.7) microg/mL (microM), respectively. The structures of these isolates were determined by spectral data including 1D and 2D NMR spectra. Compound 11 was confirmed by X-ray crystallographic analysis.
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PMID:New Sesquiterpenes from Litsea verticillata. 1276 92

Therapeutic drug monitoring (TDM) is becoming more widespread to optimize the treatment of patients with HIV/AIDS. The analytic component of TDM requires a drug assay with high specificity, small sample volume requirements, reasonable cost, and rapid turnaround time. This study modified a procedure for the concurrent measurement of 15 antiretrovirals by tandem mass spectrometry. The upper limit of the calibration curves was extended to 10,000 ng/mL, and the matrix for standards was changed from methanol to serum. Also, an additional drug, tenofovir, a nucleotide reverse transcription inhibitor, was included in the revised/improved method. Calibration curves showed good linearity between a concentration range of 100 and 10,000 ng/mL (r > 0.997 for all drugs). Accuracy was assessed by correlation of the calibrators with proficiency testing samples spiked with known drug concentrations and yielded results within 8% of the target values.
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PMID:Improved method for concurrent quantification of antiretrovirals by liquid chromatography-tandem mass spectrometry. 1450 75

The interaction of metal cyclams with carboxylate groups is thought to play an important role in their binding to the CXCR4 chemokine receptor and in their anti-HIV activity. Here we report the synthesis of acetate, phthalate, perchlorate and chloride complexes of Zn(II) cyclam (1,4,8,11-tetraazacyclotetradecane). The X-ray crystal structures of [Zn(cyclam)(phthalate)](n)(CH(3)OH)(2n) and [Zn(cyclam)(H(2)O)(2)](OAc)(2) contain octahedral Zn(II) centres. Phthalate acts as a bridging ligand in the former complex, binding through monodentate carboxylate groups, and giving rise to infinite chains in the lattice together with extensive hydrogen bonding between carboxylate donor oxygen atoms and amine and methanol acceptor atoms. The uncoordinated acetate groups and the aqua ligand in the acetate complex are also involved in a rich network of hydrogen bonds and this may account for the unusually long Zn[bond]O distance (2.27 A). In both crystalline complexes, the macrocycle adopts the trans-III (S,S,R,R) configuration. 1D (1)H NMR spectra of all four complexes have been fully assigned by a combination of 2D [(1)H, (1)H] COSY and TOCSY, and [(1)H, (13)C] and [(1 )H, (15)N] HSQC NMR data. In aqueous solution, the stable trans-III configuration found in the solid-state equilibrates slowly (hours at 298 K) with trans-I (R,S,R,S) and cis-V (R,R,R,R) configurations. The trans-III configuration is predominant in aqueous solution for both the chloride and perchlorate complexes, but for the acetate and phthalate complexes, the cis-V configuration dominates. Carboxylate groups appear to stabilize the cis-V configuration in solution through Zn(II) coordination and hydrogen bonding. Titration of the chloride Zn(II)-cyclam complex with acetate confirmed that carboxylates strongly induce formation of the cis-V configuration. This implies that carboxylates can exert a strong influence over configurational selectivity. Cyclam NH hydrogen bonding is prevalent both in the solid state and in solution, and is relevant to the anti-HIV activity of Zn(II) and other metal cyclam complexes and to their ability to recognize the CXCR4 transmembrane co-receptor.
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PMID:Selective recognition of configurational substates of zinc cyclam by carboxylates: implications for the design and mechanism of action of anti-HIV agents. 1456 77

Three new protostanes, garciosaterpenes A ( 1), B ( 2) and C ( 3), together with a new digeranylbenzophenone, garciosaphenone A ( 4) were isolated from the ethyl acetate fractions obtained from the crude methanol extracts of the trunk bark and stems of Garcinia speciosa. The structures were elucidated by spectroscopic methods and chemical reactions. Compounds 1 and 3 showed significant inhibitory activities (IC (50) 15.5 and 12.2 microg/mL, respectively) against HIV-1 reverse transcriptase and in the syncytium assay (EC (50) 5.8 microg/mL with TI 3.4 and 37.0 microg/mL with TI 1.9, respectively). Compound 4 was active in HIV-1 RT assay (IC (50) 23.9 microg/mL), but toxic in the syncytium assay. This work represents the first report on the anti-HIV-1 activities of the protostane triterpenes.
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PMID:Anti-HIV-1 protostane triterpenes and digeranylbenzophenone from trunk bark and stems of Garcinia speciosa. 1475 32

Extracts from a new chemotype of Mentha longifolia, a mint species that grows spontaneously and widely in the Moroccan mountains, were tested against human immunodeficiency virus type 1 (HIV-1). We observed that non-toxic concentrations (10 microg/mL) of extracts from this plant, in particular methanol (Ext-1) and ethyl acetate (Ext-3) extracts, significantly inhibit (p < 0.01) HIV-1BaL infection by about 40% and 55%, respectively. In addition, only Ext-3 shows significant (p < 0.008) inhibitory activity (50% inhibition) against HIV-1 reverse transcriptase. It is noteworthy that chemical analysis of these extracts suggests that flavonoids, mainly flavones of M. longifolia, may be the major inhibitors of HIV infection. In conclusion, these in vitro data suggest that components of M. longifolia may represent potential anti-HIV agents; the identification of such components is in progress.
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PMID:Human immunodeficiency virus type 1 inhibitory activity of Mentha longifolia. 1505 98

An accurate, sensitive, and specific reverse-phase high-performance liquid chromatography (HPLC) assay for the simultaneous quantitative determination of HIV-protease inhibitors (PIs) (indinavir, IDV; amprenavir, APV; saquinavir, SQV; nelfinavir, NFV; ritonavir, RTV; and lopinavir, LPV) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) (nevirapine, NVP; delavirdine, DLV; and efavirenz, EFV) in human blood plasma is described. The method provides excellent resolution and peak shape for nine analytes through a linear gradient (36-86%) of 25% phosphate buffer (pH 4.5), 60% acetonitrile, 15% methanol, and 0.75 ml TFA, with a gradient mobile phase flow rate (0.9-1.1 ml) over 30 min run time. The optimized solid phase extraction (SPE) extraction method using (1.0 ml, 100mg BOND ELUT-C18 Varian) column provides a clean base line and high extraction efficiency using a 550 microl plasma sample. The method was validated over the range of 10-10,000 ng/ml for NVP, IDV, and SQV; 10-5000 ng/ml for EFV; 25-10000 ng/ml for APV; and 25-5000 ng/ml for DLV, NFV, RTV, and LPV. This method is accurate (average accuracies of three different concentrations ranged from 91 to 112%), and precise (within- and between-day precision measures ranged from 0.2 to 5.7% and 0.1 to 5.4%, respectively). This method is suitable for use in clinical pharmacokinetic studies as well as in therapeutic drug monitoring (TDM).
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PMID:High-performance liquid chromatography assay for the quantification of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors in human plasma. 1513 96


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