Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A population pharmacokinetic model for efavirenz has been developed from therapeutic drug monitoring data in human immunodeficiency virus (HIV)-positive patients by using a nonlinear mixed-effect model. The efavirenz plasma concentrations (n = 375) of 131 patients were analyzed using high-performance liquid chromatography with UV detection. Pharmacokinetic parameters were estimated according to a one-compartment model. The effects of sex, age, total body weight, height, body mass index, and HIV treatment were analyzed. In a subgroup of 32 patients, genetic polymorphisms of the cytochrome P450 2B6 gene (CYP2B6), CYP3A4, and MDR1 were also investigated. Efavirenz oral clearance and the apparent volume of distribution were 9.50 liters/h and 311 liters, respectively. The model included only the effect of CYP2B6 polymorphisms on efavirenz clearance; this covariate reduced the intersubject variability of clearance by about 27%. Patients showing G/T and T/T CYP2B6 polymorphisms exhibited efavirenz clearances that were about 50% and 75% lower than those observed in the patients without these polymorphisms (G/G). Accordingly, to obtain EFV steady-state concentrations within the therapeutic range (1 to 4 mg/liter), it would be advisable to implement a gradual reduction in dose to 400 or 200 mg/day for patients that are intermediate or poor metabolizers, respectively. However, the remaining interindividual variability observed in the pharmacokinetic parameters of the model highlights the need for dose individualization to avoid inadequate exposure to efavirenz and suggests that these recommended doses be used with caution and confirmed by therapeutic drug monitoring and clinical efficacy. The population model can be implemented in pharmacokinetic clinical software for dosage optimization by using the Bayesian approach.
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PMID:Influence of the cytochrome P450 2B6 genotype on population pharmacokinetics of efavirenz in human immunodeficiency virus patients. 1943 61

This study was designed to investigate potential resistance mechanisms by studying the expression of resistant genes in 14 fluconazole-resistant Candida albicans isolates, with G487T and T916C mutations in the 14alpha-demethylase (ERG11) gene, collected from human immunodeficiency virus uninfected patients and a fluconazole-susceptible control strain. The in vitro susceptibilities of the C. albicans isolates to fluconazole were determined using the broth microdilution method and a disc diffusion assay. Expression of Candida drug resistance (CDR)1, CDR2, ERG11, fluconazole resistance (FLU)1 and multidrug resistance (MDR)1 genes was measured using real-time reverse transcription-polymerase chain reaction and evaluated relative to the expression of the control gene 18SrRNA. The CDR1 and CDR2 genes were upregulated in all the fluconazole-resistant C. albicans isolates, whereas only a few isolates showed high expression of MDR1, FLU1 and ERG11 genes compared with the control strain. In conclusion, overexpression of the CDR1 and CDR2 genes may play an important role in fluconazole-resistant C. albicans with G487T and T916C mutations.
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PMID:Overexpression of CDR1 and CDR2 genes plays an important role in fluconazole resistance in Candida albicans with G487T and T916C mutations. 2051 67

Human immunodeficiency virus (HIV) protease inhibitors (PIs) produce profound and unpredictable drug-drug interactions (DDIs) that cannot be explained fully by their inhibition/inactivation of CYP3A enzymes. Delineating and quantifying the CYPs and transporters inducible by PIs are crucial in developing an integrative mechanistic understanding and prediction of PI-based DDIs. To do so, two LC-MS/MS cocktail assays were modified and validated simultaneously to quantify the CYP activity of CYP3A, 2B6, 2C8, 2C9, 2C19, 1A, 2E1, 2A6 and 2D6 enzymes. These new assays were applied to evaluate the induction potential of eight PIs in microsomes isolated from PI-treated human hepatocytes. The mRNA expression of these CYPs and transporters (OATP1B1, OATP1B3, OATP1A2, MDR1, MRP2 and MRP4) was also evaluated using relative RT-PCR. The majority of PIs were net inducers of CYP3As and 2B6 at both the mRNA and activity level (> 2-fold), while ritonavir, saquinavir, nelfinavir or lopinavir did not induce CYP3A activity (< 2-fold), presumably due to CYP3A inactivation. OATP1B1 and MDR1 were the only two hepatic transporters induced (> 2-fold) by the PIs. Amprenavir was the most potent net inducer. In conclusion, our validated cocktail assays can be implemented to comprehensively quantify CYP activities in human liver microsomes and hepatocyte studies. The results also provide the much needed data on the net induction potential of the PIs for hepatic CYPs and transporters. A qualitative agreement was observed between our results and published PI-based DDIs, suggesting that human hepatocytes are a useful platform for more extensive and quantitative in vitro-in vivo prediction of PI-based DDIs.
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PMID:Quantification of human hepatocyte cytochrome P450 enzymes and transporters induced by HIV protease inhibitors using newly validated LC-MS/MS cocktail assays and RT-PCR. 2249 95

Multi-drug resistance (MDR) is still a major cause of the eventual failure of chemotherapy in cancer treatment. Different approaches have been taken to render these cells drug sensitive. Here, we attempted sensitizing drug-resistant cells from within, using a translocating immune conjugate approach. To that effect, a monoclonal antibody, C219, directed against the intracellular ATP-binding site of the membrane-anchored MDR transporter ABCB1 [P-glycoprotein (P-gp), MDR1], was conjugated to human immunodeficiency virus [HIV(37-72)Tat] translocator peptide through a disulfide bridge. Fluorescence-labelled IgG-Tat conjugates accumulated in drug resistant Chinese hamster ovary (CHO) cells within less than 20 min. Preincubation with C219-S-S-(37-72)Tat conjugate augmented calcein accumulation in drug-resistant CHO and mouse lymphoma cells, indicating reduction in ABCB1 transporter activity. A thioether conjugate C219-S-(37-72)Tat was ineffective, as were disulfide and thioether conjugates of an irrelevant antibody. Furthermore, in the presence of C219-S-S-(37-72)Tat, drug resistant cells were sensitized to colchicine and doxorubicin. Taken together, these findings demonstrate, as proof of principle, a novel approach for the reversal of MDR from within cells, by delivery of translocating immune conjugates as sensitizing agents towards chemotherapy.
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PMID:Reversing ABCB1-mediated multi-drug resistance from within cells using translocating immune conjugates. 2257 54

Pharmacogenetics refers to the effect of single nucleotide polymorphisms (SNPs) within human genes on drug therapy outcome. Its study might help clinicians to increase the efficacy of antiretroviral drugs by improving their pharmacokinetics and pharmacodynamics and by decreasing their side effects. HLAB*5701 genotyping to avoid the abacavir-associated hypersensitivity reaction (HSR) is a cost-effective diagnostic tool, with a 100% of negative predictive value, and, therefore, it has been included in the guidelines for treatment of human immunodeficiency virus (HIV) infection. HALDRB*0101 associates with nevirapine-induced HSR. CYP2B6 SNPs modify efavirenz plasma levels and their genotyping help decreasing its central nervous system, hepatic and HSR toxicities. Cytokines SNPs might influence the development of drug-associated lipodystrophy. APOA5, APOB, APOC3 and APOE SNPs modify lipids plasma levels and might influence the coronary artery disease risk of HIV-infected individuals receiving antiretroviral therapy. UGT1A1*28 and ABCB1 (MDR1) 3435C > T SNPs modify atazanavir plasma levels and enhance hyperbilirubinemia. Much more effort needs to be still devoted to complete large prospective studies with multiple SNPs genotyping in order to reveal more clues about the role played by host genetics in antiretroviral drug efficacy and toxicity.
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PMID:Can antiretroviral therapy be tailored to each human immunodeficiency virus-infected individual? Role of pharmacogenomics. 2627 78

Fluconazole is the standard treatment for oropharyngeal candidiasis, which is the third most common opportunistic infection in human immunodeficiency virus (HIV)/AIDS patients in Indonesia. Overuse of this drug could lead to the emergence of resistance. The objective of this study was to analyse the role of ERG11, CDR1, CDR2 and MDR1 gene overexpression and mutations in the ERG11 gene as a genetic mechanism of fluconazole resistance in Candida albicans isolated from HIV patients in Indonesia. Overexpression of ERG11, CDR1, CDR2 and MDR1 was analysed by real-time reverse transcription PCR, while ERG11 gene mutation analysis was performed using sequencing methods. Seventeen isolates out of 92 strains of C. albicans isolated from 108 HIV patients were found to be resistant to azole antifungals. The highest gene overexpression of ERG11 was found in C. albicans resistant to single fluconazole, while the highest gene overexpression of CDR2 was detected in all isolates of C. albicans resistant to multiple azoles. Amino acid substitutions were observed at six positions, i.e. D116E, D153E, I261V, E266D, V437I and V488I. The amino acid substitution I261V was identified in this study and was probably associated with fluconazole resistance. The combination of overexpression of CDR2 and ERG11 and mutation in the ERG11 gene was found to be a genetic mechanism of fluconazole resistance in C. albicans isolated from HIV patients in Indonesia.
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PMID:Overexpression and mutation as a genetic mechanism of fluconazole resistance in Candida albicans isolated from human immunodeficiency virus patients in Indonesia. 2629 39

To investigate the method of separating human pancreatic cancer stem cells by Hoechst 33342 labeled flow cytometry and to analyze the biological properties of pancreatic cancer stem cells. The human pancreatic cancer cell line PC-3 was divided into SP and non-SP cells by flow cytometry. The number of two cell clone spheres and nude mice tumor formation rates were compared by cultivating in serum-free medium; The expression of CD133, Nestin mRNA and protein was analyzed by real-time fluorescence quantitative PCR and Western blot; The expression of two cell drug resistance genes (MDR1, ABCG2, ABCA2 and MRP1) was analyzed by real time fluorescent quantitative PCR. The number of the cloned spheres in SP cells in serum-free medium was significantly higher than that of non-SP cells (P<0.05). The incidence of SP cells in the tumor of immunodeficiency nude mice was significantly higher than that of non-SP cells, and the difference was statistically significant (P<0.05). Real-time fluorescence quantitative PCR analysis showed that the expression of CD133 and Nestin mRNA in SP cells was significantly higher than those of non-SP cells, and the expression of CD133 and Nestin protein in SP cells was also significantly higher than those of non-SP cells (P<0.05). In conclusion, SP side population pancreatic cancer cells by Hoechst 33342 separation have the stem cell characteristics, higher tumor formation rate and higher drug resistance, which may be related to chemotherapy resistance.
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PMID:Establishment of pancreatic cancer stem cells by flow cytometry and their biological characteristics. 2661 45


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