ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Potassium perchlorate has been used at various times during the last 50 years to treat hyperthyroidism. Since World War II ammonium perchlorate has been used as a propellant for rockets. In 1997, the assay sensitivity for perchlorate in water was improved from 0.4 mg/L (ppm) to 4 &mgr;g/L (ppb). As a result, public water supplies in Southern California were found to contain perchlorate ions in the range of 5 to 8 ppb, and those in Southern Nevada were found to contain 5 to 24 ppb. Research programs have been developed to assess the safety or risk from these exposures and to assist state and regulatory agencies in setting a reasonable safe level for perchlorate in drinking water. This report reviews the evidence on the human health effects of perchlorate exposure. Perchlorate is a competitive inhibitor of iodine uptake. All of its pharmacologic effects at current therapeutic levels or lower are associated with inhibition of the sodium-iodide symporter (NIS) on the thyroid follicular cell membrane. A review of the medical and occupational studies has been undertaken to identify perchlorate exposure levels at which thyroid hormone levels may be reduced or thyrotropin levels increased. This exposure level may begin in the 35 to 100 mg/d range. Volunteer studies have been designed to determine the exposure levels at which perchlorate begins to affect iodine uptake in humans. Such effects may begin at levels of approximately 1 mg/d. Environmental studies have assessed the thyroidal health of newborns and adults at current environmental exposures to perchlorate and have concluded that the present levels appear to be safe. Whereas additional studies are underway both in laboratory animals and in the field, it appears that a safe level can be established for perchlorate in water and that regulatory agencies and others are now trying to determine that level.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The authors assessed the impact of protease and reverse transcription (RT) mutations and individual pharmacokinetic parameters on virologic response to a four-drug regimen including ritonavir/saquinavir. Treatment was given at the start of the study (M0) to 22 HIV-1 protease inhibitor-naive or pretreated patients. Protease and RT genes were sequenced at M0, at the time of virologic failure, or at the end of the follow-up. Plasma ritonavir and saquinavir peak Cmax, Cmin, and area under the curve (AUC) were determined based on samples taken 0, 1, 2, 3, 4, 6, 8, and 12 hours after administration. HIV-1 RNA decreased to less than 50 copies/mL in 11 patients (group 1). At M0, five of them had no RT mutation and 10 had three or fewer secondary protease mutations with no new mutation during follow-up. Ritonavir and saquinavir pharmacokinetics showed wide interindividual variability. Treatment failed in 11 patients (group 2): 9 had three to eight protease mutations and a mean of 5.8 RT mutations at M0, with emergence of new mutations during follow-up. Pharmacokinetics was similar to those of group 1. The other two patients with virologic failure showed no baseline primary mutation but were the only patients with insufficient saquinavir and ritonavir AUC. The authors showed the complementarity between drug-resistance genotype and individual pharmacokinetics and the potential utility of AUC and Cmaxto manage treatment.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Genotyping of polymorphic drug metabolizing enzymes may be useful to estimate the blood concentration, efficacy, and toxicity of drugs before administration. Blood samples are most generally used for genotyping; however, sampling is invasive and complicated by handling and transport. Therefore, the authors developed genotyping methods using nonblood specimens, and then each genotype was compared with that from blood. Healthy Japanese volunteers provided hairs (n = 50), buccal cell swabs (n = 50), and fingernails (n = 30) forN-acetyltransferase 2andCYP2C19genotyping. Recovery of genomic DNA from each nonblood specimen was lower than that from 0.5 mL blood. Using a modification of the DNA extraction and polymerase chain reaction amplification method, genotypes were diagnosed without failure, even for those with very low levels of DNA. Both genotypes from these specimens completely matched the genotypes from the blood of the same subject. These nonblood specimens can be convenient, accessible, and economical alternatives to blood as a source of DNA for genotyping.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The authors have determined the frequency of intracellular interleukin-2 (IL-2) and interferon-&ggr; (IFN-&ggr;) synthesis by T-cell subsets in whole blood (WB) and isolated lymphocytes in 16 transplant recipients treated with tacrolimus and 10 control patients who were not transplant recipients. The authors also determined the impact of varying amounts of red blood cells (RBC) on immunosuppression by tacrolimus. Samples were analyzed by two-color flow cytometry, and the results were expressed as a ratio of whole blood to isolated lymphocytes. In healthy subjects who were not transplant recipients, the frequency of IL-2–producing CD8−and CD8+cells was higher in WB than in isolated lymphocytes (mean ± SD of whole blood to lymphocytes ratio: 1.24 ± 0.5 and 1.67 ± 0.62, respectively). Adding varying amounts of RBC had no significant impact on IL-2 production by CD8−and CD8+T cells. Adding tacrolimus (10 ng/mL) to lymphocyte cultures inhibited (90%) IL-2 production in isolated T cells but not in the whole-blood assay. The dose of tacrolimus required for a 50% inhibition of IL-2 release in T cells was 10-fold higher in cultures with RBC than without. Peripheral blood mononuclear cells (PBMC) isolated from tacrolimus-treated whole blood (WB) showed less IL-2 inhibition than did lymphocytes in the WB. The authors also tested cytokine production in WB and PBMCs in 16 transplant recipients and observed various patterns of reactivity. The frequency of IL-2–producing CD8−and CD8+cells was similar using two different methods in 10 of 16 patients tested. By contrast, in the remaining six patients the authors observed a significant inhibition of IL-2 production in both CD8−and CD8+T-cell subsets in the whole-blood assay but not in the isolated lymphocytes. The frequency of CD8−IFN-&ggr;–producing cells was significantly lower in 9 of 16 patients, but the same individuals showed no inhibition of their CD8+IFN-&ggr; T cells. The trough levels of tacrolimus did not predict the level of cytokine inhibition in the whole-blood assay in these patients. The authors' results show that the whole-blood assay for cytokine production can be used for monitoring the in vivo effect of tacrolimus in transplant recipients.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The authors studied the interactive effects of the coadministration of haloperidol and chlorpromazine on plasma concentrations of haloperidol and reduced haloperidol. The subjects were 43 Japanese male schizophrenic inpatients who were concomitantly treated with chlorpromazine before or after monotherapy with haloperidol. Coadministration of chlorpromazine produced significant increases in the plasma concentrations of haloperidol (P < 0.01) and reduced haloperidol (P < 0.001) by an average of 28.5% ± 83.3% and 160.8% ± 288.9%, respectively. However, there were marked interindividual variations in the interactive effects of chlorpromazine. The authors analyzed the importance of five CYP2D6 genotypes,*1/ *1, *1/ *10, *10/ *10, *1/*5,and*5/*10on the percentage of change in plasma concentrations of haloperidol and reduced haloperidol. Patients with theCYP2D6*5allele (n = 4) showed a significantly smaller increase in plasma concentrations of haloperidol (P < 0.05) and a slightly smaller increase in those of reduced haloperidol (P = 0.074) in response to the coadministration of chlorpromazine compared than those with theCYP2D6*1/*1genotype (n = 8). Those with theCYP2D6*1/*1genotype (n = 8) showed a trend toward greater increases in plasma concentrations of haloperidol than those with other genotypes (P = 0.087).

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Grapefruit juice (GJ), a cytochrome P450 (CYP) 3A4 inhibitor, may affect the pharmacokinetics of drugs metabolized through CYP 3A4. Losartan, an angiotensin II antagonist, is converted into its main active metabolite E3174 by CYP 3A4 and CYP 2C9. The effect of GJ on losartan pharmacokinetics was assessed in a randomized crossover trial. Losartan was given to 9 volunteers with and without GJ. Concentrations of losartan and its E3174 metabolite were determined in serum by a high-performance liquid chromatography method (HPLC). Significant differences were observed in some of the pharmacokinetic parameters of losartan and its metabolite E3174 after losartan administration with and without co-administered GJ. The lag time (time to drug appearance in serum) of losartan increased significantly with co-administered GJ. The mean residence time (MRT) and half-life (t1/2) of the E3174 metabolite were significantly longer and the area under the concentration–time curve (AUC) of the E3174 metabolite was significantly smaller after concomitant GJ administration. The ratio AUClosartan/AUCE3174was significantly increased after concurrent grapefruit juice intake. The increased lag time of losartan and the increased MRT and t1/2and decreased AUC of E3174 were considered indicative of simultaneous CYP 3A4 inhibition and P-glycoprotein activation. The significantly increased AUClosartan/AUCE3174ratio, however, indicates reduced losartan conversion to E3174 by CYP 3A4 metabolism as a result of co-administered GJ.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Removal of the oxcarbazepine metabolite 10-hydroxycarbazepine (MHD) by plasmapheresis was evaluated during a series of six plasmaphereses of a 13-year-old boy with Rasmussen encephalitis. Plasmapheresis was performed after steady-state concentrations of MHD had been achieved with a dose of 2550 mg oxcarbazepine daily. The mean amount of MHD removed per plasmapheresis was 78.9 mg (SD: 6.0 mg), representing 3% to 4% of the daily oxcarbazepine dose and approximately 5% to 6% of body stores of MHD. The mean steady-state trough MHD concentration was 33.3 mg/L (SD: 1.8 mg/L), and this was remarkably stable during the entire plasmapheresis period. The serum concentration of MHD was only mildly reduced by the procedure. The areas under the concentration curve of MHD on the first and sixth day of plasmapheresis were 99% and 94%, respectively, of the pre-plasmapheresis values. The results are in agreement with studies on other anticonvulsant medications (carbamazepine, valproic acid, phenobarbital, and phenytoin), indicating that minor fractions (2% to 10%) of body stores of these drugs are depleted during plasmapheresis. The authors conclude that it is unnecessary to adjust the oxcarbazepine dosage when performing single-volume plasma exchanges or even multiple exchanges during an extended period. It is further proposed that plasmapheresis is unlikely to be of therapeutic benefit in the treatment of an oxcarbazepine overdose.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

An analytical technique using liquid chromatography (LC) coupled with electrospray–mass spectrometry (ESI–MS) has been developed for the simultaneous determination of five protease inhibitors (PIs): saquinavir, indinavir, ritonavir, nelfinavir, and amprenavir; and three non-nucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine, delavirdine, and efavirenz, in human plasma. This assay allows the elution and identification of these drugs in a single run (10 minutes) using a linear gradient with water and acetonitrile. The procedure involves liquid–liquid extraction. High-performance liquid chromatography (HPLC) separation was achieved on a C18 reversed-phase column, with a linear gradient elution followed by mass spectrometry detection. The calibration curves, obtained by automatic process peak area integration, show a good linearity in a range of concentrations between 20 and 10,000 ng/mL (40–10,000 ng/mL for efavirenz). The limit of detection was approximately 10 ng/mL for seven drugs (25 ng/mL for efavirenz). The coefficients of variation (CV) were always less than 15% for both intraday and interday precision for each compound. The recovery of the eight drugs ranged from 88.5% to 100%. This novel LC/ESI–MS assay provides an excellent method for simultaneous quantitative monitoring of different components of the highly active antiretroviral treatments (HAARTs) in patients treated simultaneously with PIs and NNRTIs, and it has been successfully applied to therapeutic drug monitoring and pharmacokinetic studies.

ISSN:0163-4356    

出版商:OVID    

年代:2001

数据来源: OVID