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)

The development of HPLC-atmospheric pressure ionization-mass spectrometry (HPLC-MS) has presented clinical laboratories with a powerful analytic tool. The aim of this paper is to provide an overview of the current status of HPLC-MS in the clinical laboratory; to discuss the challenges to mass spectrometry in this setting; and to present some of the latest developments in instrumentation and illustrate their potential application. Currently, the major clinical applications for HPLC-MS are neonatal screening for metabolic disorders, therapeutic drug monitoring of immunosuppressant and HIV/AIDS drugs, and toxicological investigations. The major barrier to the uptake of this technology in the clinical laboratory is the initial capital outlay for instrumentation. A secondary reason is the lack of suitably trained scientists. The challenges that clinical HPLC-MS face are (I) ease of use and automation, (2) interpatient variability in relation to matrix effects, (3) availability of suitable internal standards, and (4) harmonization of methods to meet regulatory requirements. The development of the triple quadrupole linear ion trap mass analyzer allows the quantification power of a triple quadrupole mass analyzer to be combined with the scanning ability of an ion trap.This hybrid instrument allows different permutations of scan combinations. The combination of selected reactant monitoring and MS3 is an attractive combination for quantification. The ion source, atmospheric pressure photoionization, has recently been developed and is well suited to nonpolar analytes, although its role is yet to be established. This ion source complements other interfaces used in HPLC-MS. Both of these advances in instrumentation add to the potential applications of HPLC-MS. How HPLC-MS goes forward into the clinical laboratory is dependent on clinical scientists, instrument manufacturers, and regulatory authorities.
Ther Drug Monit 2005 Dec
PMID:High-performance liquid chromatography-mass spectrometry in the clinical laboratory. 1640 95

An improved HPLC fluorimetric method for the quantification of enfuvirtide in plasma of HIV-infected subjects was described and validated. The use of an internal standard improved the reproducibility and precision of the analysis. Our method showed lower limits of detection and quantification (LOD = 32 ng/mL, LOQ = 78 ng/mL), lower intraday (RSD% 1.25-2.95) and interday (RSD% 1.75-4.69) coefficients of variation, greater recovery (>100%), lower duration (16 minutes) and lower cost than previously described fluorimetric methods. Therefore, this method can be used as a reliable tool for pharmacokinetic studies of enfuvirtide.
Ther Drug Monit 2006 Feb
PMID:An improved HPLC fluorimetric method for the determination of enfuvirtide plasma levels in HIV-infected patients. 1641 4

Nanobacteria are best described as 60-300 nm nanovesicles. In the body they collect calcium and phosphate to form apatite, adhere to cells, or invade them--processes regulated by a slime based on proteins (primordial proteins). A versatile functionality realized with a minimum of properties equips nanobacteria with a unique survival potential. They were identified in humans, animals, wastewater and the stratosphere. In South Africa they were detected in people infected with HIV. Models indicate that they boost the genetic diversity of the HIV-1 virus. Experiments showed that they are excreted via urine, explaining their presence in the environment. Eradication would be virtually impossible if they had an extraterrestrial origin, implying a permanent bombardment from space. Whereas the biological status of nanobacteria is still not clarified, we postulate here that the native habitat of nanobacteria are mammals, suggesting that at least modern species have their origin on Earth. The thesis results from mapping functions and properties of the slime, and could facilitate the localisation of nanobacterial reservoirs, identification of local distribution routes and tracking of global transport cycles. Agricultural irrigation with water containing excreta from humans infected with nanobacteria could be a central disseminator of the nanobioaerosols.
J Environ Monit 2006 Mar
PMID:Nanobioaerosols--reconsidering agricultural irrigation in a warming world. 1652 17

The APOBEC (acronym for apolipoprotein B editing catalytic polypeptide) family of cytidine deaminases are widely distributed in the biological world and play a central role in diverse enzymatic pathways. Members of this family (APOBEC3G and APOBEC3F) have been recently shown to be able to restrict HIV-1 replication in physiologically relevant target cells (macrophages, lymphocytes), presumably by triggering extensive deamination of the viral RNA/DNA replication intermediates. This natural antiretroviral host defense mechanism is counteracted by the HIV-1 protein Vif, which is able to target APOBECs to degrade. The so-called "Vif/APOBEC3G paradigm" has been confirmed by a growing literature. However, evidence arising from recent studies has expanded this view, showing that the replication of other viruses is also restricted by APOBEC family members and suggesting antiviral mechanism(s) of action unrelated to the catalytic activity of these proteins. Furthermore, evolutionary investigations on primates have shown that APOBEC3 gene expansion might be related to an ancient adaptive selection to prevent endogenous genetic instability, indicating an additional ancient protective role of APOBECs. This article is aimed at broadening the current knowledge about the antiviral activity of the APOBEC members and to highlight the notion that their role(s) might be more general than previously anticipated.
Med Sci Monit 2006 May
PMID:APOBEC deaminases as cellular antiviral factors: a novel natural host defense mechanism. 1664 89

Total plasma concentrations are currently measured for therapeutic drug monitoring of HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). However, the pharmacological target of antiretroviral drugs reside inside cells. To study the variability of their cellular accumulation, and to determine to which extent total plasma concentrations (TPC) correlate with cellular concentrations (CC), plasma and peripheral blood mononuclear cells (PBMCs) were simultaneously collected at single random times after drug intake from 133 HIV infected patients. TPC levels were analysed by high-performance liquid chromatography with ultraviolet detection and CC by LC-MS/MS from peripheral blood mononuclear cells. The best correlations between TPC and CC were observed for nelfinavir (NFV, slope=0.93, r=0.85), saquinavir (SQV, slope=0.76, r=0.80) and lopinavir (LPV, slope=0.87, r=0.63). By contrast, TPC of efavirenz (EFV) exhibited a moderate correlation with CC (slope=0.69, r=0.58), while no correlation was found for nevirapine (NVP, slope=-0.3, r=0.1). Interindividual variability in the CC/TPC ratio was lower for protease inhibitors (coefficients of variation 76%, 61%, and 80% for SQV, NFV and LPV, respectively) than for nonnucleoside reverse transcriptase inhibitors (coefficients of variation 101% and 318%, for EFV and NVP). As routine CC measurement raises practical difficulties, well-correlated plasma concentrations (ie, NFV, SQV and LPV) can probably be considered as appropriate surrogates for cellular drug exposure. For drugs such as EFV or NVP, there may be room for therapeutic drug monitoring improvement using either direct CC determination or other predictive factors such as genotyping of transporters or metabolizing enzyme genes.
Ther Drug Monit 2006 Jun
PMID:Are plasma levels valid surrogates for cellular concentrations of antiretroviral drugs in HIV-infected patients? 1677 16

Because HIV medications are used in combination, it is important to develop multiplex assays to streamline the therapeutic drug monitoring process and provide rapid turnaround. This article reports full validation of an analytical method that combines atazanavir with 6 HIV-protease inhibitors (indinavir, amprenavir, saquinavir, nelfinavir, ritonavir, and lopinavir) and 2 nonnucleoside reverse transcriptase inhibitors (nevirapine and efavirenz). Using 200 microL of plasma and a simple liquid-liquid extraction method, this analytical method achieved a clean baseline and high extraction efficiencies (90.0% to 99.5%). A Zorbax C-18 (150 x 4.6 mm, 3.5 microm) analytical column was used along with a 27-minute linear gradient elution of the mobile phase to provide sharp peaks at 210 nm. This method was validated over a range of 25 to 10,000 ng/mL and is accurate (90.4% to 110.5%) and precise (precision within a day and between days ranged from 2.3% to 8.3%). Because this method is simple and inexpensive, it may have applicability in countries with low resources.
Ther Drug Monit 2006 Aug
PMID:Full validation of an analytical method for the HIV-protease inhibitor atazanavir in combination with 8 other antiretroviral agents and its applicability to therapeutic drug monitoring. 1688 19

Lopinavir is one of the most-widely used protease inhibitors in the treatment of HIV-1 infected patients. Concentration-effect relationships have been described for both antiviral activity and toxicity. Less is known about patient characteristics that may determine interpatient variability in lopinavir plasma concentrations. A database was created containing all Therapeutic Drug Monitoring (TDM) results collected at our Department. Patients were included if they were using lopinavir twice daily for at least two weeks; subjects who were known to be nonadherent (based on either a lopinavir concentration <0.2 mg/L or suspected by the physician) were excluded. Demographic data were collected from TDM application forms and patient charts. Patients attending one of the 22 HIV treatment centers in The Netherlands. The Department of Clinical Pharmacy is a national referral center for TDM of antiretroviral agents. Lopinavir concentration ratios (CRs) were calculated for each patient by dividing the individual plasma concentration by the time-adjusted population value. Relationships with lopinavir CRs were tested using regression analysis and analysis of variance. A total of 802 patients were included (607 males; 150 females; 45 unknown). The age and body weight of the patients ranged from 18 to 74 years (mean 42) and 42 to 121 kg (mean 72), respectively. Race was known for 756 persons: Caucasian 76%, African 18% and Asian 6%. The median (+ interquartile range, IQR) lopinavir CR was 0.98 (IQR: 0.67-1.31). Body weight showed an inverse relationship with lopinavir CR (F = 23.1; P < 0.001). Age was not related with lopinavir CR (P = 0.99). Female patients had a significantly higher lopinavir CR than males: 1.18 vs. 1.03 (P = 0.005); race was not associated with differences in lopinavir CR. In a multivariate regression analysis body weight, but not gender, remained significantly related to lopinavir CR. Body weight is the only demographic factor that could be related to lopinavir exposure; clinicians should be alert for an increased risk of suboptimal antiviral efficacy in patients with high body weight, and for an increased risk of toxicity in patients with a low body weight.
Ther Drug Monit 2006 Oct
PMID:A retrospective TDM database analysis of interpatient variability in the pharmacokinetics of lopinavir in HIV-infected adults. 1703 80

Atazanavir (ATV) and lopinavir (LPV) are widely used HIV-1 protease inhibitors. Like with other protease inhibitors, careful monitoring of potential drug-drug and drug-disease interactions in clinical practice is necessary. The aim of this study was to assess the impact of substance use and hepatitis virus coinfection on plasma ATV and LPV trough concentrations in HIV-positive substance users and nonusers. Individuals established on ATV (300 mg and 100 mg ritonavir daily) or LPV (400 mg and 100 mg ritonavir twice daily)-containing regimens completed two clinical visits (trough and directly observed therapy) during which dosing characteristics, concomitant medication, and substance use were recorded. Trough plasma concentrations (22-26 hours for ATV and 10-14 hours for LPV) were measured using LCMSMS. The influence of substance use was evaluated by Kruskal-Wallis test. Substance use was associated with a marked decrease in trough LPV concentrations during the trough visit (median, 5.536 and 3.791 microg/mL for nonsubstance users and substance users, respectively, P = 0.029). Significantly lower LPV trough levels were also noted among patients with active hepatitis C virus coinfection evaluated as an independent variable (median, 2.253 and 5.927 microg/mL for active and inactive/no hepatitis C virus infection, respectively, P = 0.032). Substance use and hepatitis virus coinfection had limited effects on ATV trough levels. In this cohort, despite the wide interindividual variability of ATV and LPV trough concentrations, significant associations between substance use and active hepatitis C virus infection and low LPV trough concentrations were observed. Further work is needed to assess the optimal dosing regimen when using LPV in HIV-infected substance users.
Ther Drug Monit 2007 Oct
PMID:Assessing the impact of substance use and hepatitis coinfection on atazanavir and lopinavir trough concentrations in HIV-infected patients during therapeutic drug monitoring. 1789 44

Data on the concentrations of didanosine (ddI) and tenofovir (TFV) in seminal plasma are sparse. Subtherapeutic drug concentrations within the lumen of the male genital tract may have implications for selection and transmission of drug-resistant HIV strains. On the other hand, sufficient penetration of these drugs into the male genital tract has potential toxic effects on the spermatozoa and their precursors. In the current study, the authors obtained paired semen and blood samples at variable time points after drug intake from 30 HIV-1-infected patients using a ddI (n = 15) or ddI + TFV (n = 15) containing an antiretroviral regimen. Didanosine and TFV concentrations were measured in seminal and blood plasma and semen quality was assessed. Both ddI and TFV penetrated well into seminal plasma. Whereas blood plasma ddI concentrations dropped to near or below the lower limit of quantification of 0.017 microg/mL 9 hours after drug intake, the ddI concentration in seminal plasma remained detectable during the whole dosing interval with a median of 0.20 and 0.21 microg/mL in the ddI and ddI + TFV groups, respectively. Tenofovir was detectable during the whole dosing interval in both blood and seminal plasma with a median concentration of 0.12 and 0.25 microg/mL, respectively, and a median seminal-to-blood-plasma ratio of 3.3. Semen quality was within the normal range according to the criteria of the World Health Organization, except for the percentage of progressively motile sperm, which was low in both groups of patients. The authors conclude that ddI and TFV penetrate well into seminal plasma and that the reduced sperm motility deserves further study.
Ther Drug Monit 2007 Oct
PMID:Semen quality and drug concentrations in seminal plasma of patients using a didanosine or didanosine plus tenofovir containing antiretroviral regimen. 1789 45

Gene therapy is anticipated as being an important medical development. Essential to its effectiveness is the appropriate activity (protein expression) in the expected target cells. A noninvasive diagnostic procedure of successful gene expression will be of paramount importance to validate its use or its misuse (eg, sports gene doping). Externally detectable labeled oligonucleotide hybridizing with the messenger RNA generated by the transferred gene has been proposed as a possibility to monitor successful gene therapy. The authors selected the erythropoietin gene (Epo) for a pilot study on erythropoietin protein expression in mouse muscle. Oligonucleotides of peptide nucleic acid (PNA) type capable of antisense binding to unique murine Epo-mRNA sequences were synthesized by solid phase methods, and elongated at the N-terminus with the HIV Tat (48-60) cell penetrating peptide. They were labeled with fluorescence and radioactive tags to verify penetration and longer half-life properties in Epo gene transfected C2C12 mouse muscle cells as compared with corresponding wild-type cells. Downregulation of newly expressed erythropoietin protein in such cells additionally confirmed the penetration and hybridizing properties of the selected labeled oligonucleotide. I-labeled Tat-PNAs were intravenously injected into mice that had previously received the Epo gene into the right tibialis muscle by DNA electrotransfer. Preferential accumulation of radioactivity in the transferred limb as compared with the contralateral limb was ascertained, especially for I-Tat-CTA CGT AGA CCA CT (labeled Tat-PNA 1). This study provides experimental data to support the potential use of external noninvasive image detection to monitor gene therapy. The extension of the approach to more sensitive methods for whole-body external detection such as positron emission tomography appears feasible.
Ther Drug Monit 2007 Oct
PMID:Monitoring gene therapy by external imaging of mRNA: pilot study on murine erythropoietin. 1789 52


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