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1. |
Acyl Glucuronide Drug Metabolites: Toxicological and Analytical Implications |
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Therapeutic Drug Monitoring,
Volume 25,
Issue 1,
2003,
Page 1-16
Maria Shipkova,
Victor Armstrong,
Michael Oellerich,
Eberhard Wieland,
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摘要:
Although glucuronidation is generally considered a detoxification route of drug metabolism, the chemical reactivity of acyl glucuronides has been linked with the toxic properties of drugs that contain carboxylic acid moieties. It is now well documented that such metabolites can reach appreciable concentrations in blood. Furthermore, they are labile, undergo hydrolysis and pH-dependent intramolecular acyl migration to isomeric conjugates of glucuronic acid, and may react irreversibly with plasma proteins, tissue proteins, and with nucleic acids. This stable binding causes chemical alterations that are thought to contribute to drug toxicity either through changes in the functional properties of the modified molecules or through antigen formation with subsequent hypersensitivity and other immune reactions. Whereas in vitro data on the toxicity of acyl glucuronides have steadily accumulated, direct evidence for their toxicity in vivo is scarce. Acyl glucuronides display limited stability, which is dependent on pH, temperature, nature of the aglycon, and so on. Therefore, careful sample collection, handling, and storage procedures are critical to ensure generation of reliable pharmacologic and toxicologic data during clinical studies. Acyl glucuronides can be directly quantified in biologic specimens using chromatographic procedures. Their adducts with plasma or cell proteins can be determined after electrophoretic separation, followed by blotting. ELISA techniques have been used to assess the presence of antibodies against acyl glucuronide–protein adducts. This review summarizes the most recent evidence concerning biologic and toxicologic effects of acyl glucuronide metabolites of various drugs and discusses their relevance for drug monitoring. A critical evaluation of the available methodology is included.
ISSN:0163-4356
出版商:OVID
年代:2003
数据来源: OVID
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2. |
Utility of Antiepileptic Drug Monitoring in the Pediatric Emergency Department |
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Therapeutic Drug Monitoring,
Volume 25,
Issue 1,
2003,
Page 17-21
Eran Kozer,
Dennis Scolnik,
Whitty Agamata,
Shelly Weiss,
Zulfikaral Verjee,
Gideon Koren,
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摘要:
Convulsive disorders are common in the pediatric age group, and measurement of serum concentration of an antiepileptic drug (AED) is frequently ordered for epileptic patients in the emergency department (ED). The objective of this study was to develop a better understanding of the indications for, and consequences of, monitoring AED serum concentrations in the pediatric ED. Charts of 116 patients who visited the ED and were tested for blood levels of AED were retrospectively reviewed. Main outcome measures were number and percentage of levels outside the therapeutic range, discontinuation of an AED or introduction of a new one, dosage modifications, and admission to hospital. Two pediatricians and a pediatric neurologist aware only of patients' age, weight, diagnosis, history, clinical presentation, and drug details reviewed each case and on the basis of predetermined criteria decided whether measurement of AED was indicated. Mean age (± SD) of the study population was 7 ± 5 years (range, 2 months–17 years). Forty-two patients (36%) were on monotherapy, and 74 (64%) were on polytherapy. Sixty-eight patients (59%) presented with increased seizure frequency, 7 (6%) with status epilepticus, and 13 (11%) with suspected AED toxicity. The remainder of the children presented with problems unrelated to epilepsy. No significant difference was found between patients with AED levels within the therapeutic range and those with levels outside it in the proportion of children needing dosage change, change in medication, or hospital admission (P= 0.5, 0.8, and 0.8, respectively). None of the patients presenting with status epilepticus and only 15% of those with increased seizure activity had subtherapeutic levels. Review of the cases suggested that measuring serum AED level was not indicated in 57 (49.1%) patients. In the pediatric ED, abnormal AED levels do not correlate with clinical management. Before ordering tests, physicians should consider whether their results would alter patient treatment.
ISSN:0163-4356
出版商:OVID
年代:2003
数据来源: OVID
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3. |
Quantification of Immunosuppression by Flow Cytometry in Stable Renal Transplant Recipients |
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Therapeutic Drug Monitoring,
Volume 25,
Issue 1,
2003,
Page 22-27
Mario Stalder,
Tudor Bîrsan,
Bari Holm,
Mojgan Haririfar,
John Scandling,
Randall Morris,
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摘要:
The current standard of monitoring transplant patients by drug levels is not optimal because it does not take into account the different and individual effects of immunosuppressive drugs on each patient. In this study, the authors tested immune function assays for monitoring transplant patients. Blood was collected from stable renal transplant patients treated with cyclosporin, mycophenolate mofetil, and prednisone (n = 8), and from healthy volunteers (n = 12). Lymphocyte proliferation, expression of T-cell surface activation antigens (CD25, CD71, CD11a, CD95, CD154), production of intracellular cytokines (IL-2, INF&ggr;, TNF&agr;), and lymphocyte subsets (CD4, CD8, CD16, CD20) were assessed by flow cytometry. Lymphocyte proliferation, expression of T-cell surface activation antigens, and production of intracellular cytokines were significantly decreased in transplant recipients compared with healthy control volunteers. The combined effects of several immunosuppressive drugs in renal transplant recipients can be quantitated with immune function assays in whole blood. This new method may be helpful to achieve an optimal level of immunosuppression for each patient.
ISSN:0163-4356
出版商:OVID
年代:2003
数据来源: OVID
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4. |
Bayesian Forecasting of Oral Cyclosporin Pharmacokinetics in Stable Lung Transplant Recipients With and Without Cystic Fibrosis |
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Therapeutic Drug Monitoring,
Volume 25,
Issue 1,
2003,
Page 28-35
A. Rousseau,
C. Monchaud,
J. Debord,
I. Vervier,
M. Estenne,
P. Thiry,
P. Marquet,
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摘要:
The aims of the current study were (1) to study Neoral pharmacokinetics (PK) in stable lung recipients with or without cystic fibrosis (CF), (2) to compare Neoral PK between these two groups, and (3) to design Bayesian estimators for PK forecasting and dose adjustment in these patients using a limited number of blood samples. The individual PK of 19 adult lung transplant recipients, 9 subjects with CF and 10 subjects without CF, were retrospectively studied. Three profiles obtained within 5 days were available for each patient. A PK model combining a gamma distribution to describe the absorption profile and a two-compartment model were applied. Different exposure indices were estimated using nonlinear regression and Bayesian estimation. The PK model developed reliably described the individual PK of Neoral in lung transplant patients with and without CF, and the values of the first and second half-lives were different in these two populations (&lgr;1= 4.14 ± 3.01 vs. 2.16 ± 1.75 h−1;P< 0.01; &lgr;2= 0.36 ± 0.11 vs. 0.49 ± 0.12 h−1;P< 0.01), while the mean absorption time and standard deviation of absorption time tended to be less in patients with cystic fibrosis (P< 0.1). Also, the patients with CF required higher doses than those without CF to achieve similar drug exposure. Consequently, population modeling was performed in CF and non-CF patients separately. Bayesian estimation allowed accurate prediction of AUC0–12, AUC0–4, Cmax, and Tmaxusing three blood samples collected at T0h, T1h, and T3h in both groups. This study demonstrated the applicability and good performance of the PK model previously developed for oral cyclosporin and of the MAP Bayesian estimation of cyclosporin systemic exposure in CF and non-CF patients. Moreover, it is the first to propose a monitoring tool specifically designed for cyclosporin monitoring in patients with CF.
ISSN:0163-4356
出版商:OVID
年代:2003
数据来源: OVID
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5. |
A Bayesian Method Based on Clotting Factor Activity for the Prediction of Maintenance Warfarin Dosage Regimens |
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Therapeutic Drug Monitoring,
Volume 25,
Issue 1,
2003,
Page 36-40
Maria Pitsiu,
Eva Parker,
Leon Aarons,
Malcolm Rowland,
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摘要:
A Bayesian algorithm, employing a population pharmacokinetic–pharmacodynamic model, for the effective and rapid prediction of warfarin maintenance dosing requirements was developed. The algorithm was evaluated prospectively in five healthy volunteers who were given a 15-mg single dose of racemic warfarin. Based on previous population pharmacokinetic and pharmacodynamic parameters and factor VII response measurements taken during the first 48 hours, dosage regimens to achieve a subtherapeutic degree of anticoagulation (50% of normal) were determined. Three factor VII response measurements were sufficient to determine dosing requirements in the five volunteers. The advantage of the algorithm is that it does not require warfarin concentration measurements and uses non–steady-state data.
ISSN:0163-4356
出版商:OVID
年代:2003
数据来源: OVID
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6. |
Cross-Reactivity Assessment of Carbamazepine-10,11-epoxide, Oxcarbazepine, and 10-Hydroxy-Carbazepine in Two Automated Carbamazepine Immunoassays: PETINIA and EMIT 2000 |
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Therapeutic Drug Monitoring,
Volume 25,
Issue 1,
2003,
Page 41-45
François Parant,
Hubert Bossu,
Marie Gagnieu,
Gisèle Lardet,
Mustapha Moulsma,
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摘要:
This study was conducted to compare the cross-reactivity of two commercially available carbamazepine (CBZ) immunoassays (PETINIA and EMIT 2000) with carbamazepine-10,11-epoxide (CBZ-E), the active metabolite of CBZ. Oxcarbazepine (OCBZ) and its main metabolite 10-hydroxy-carbazepine (HCBZ) have a chemical structure closely related to that of CBZ. The cross-reactivities of these two drugs were also investigated. In the first part of the study, Lyphocheck blank human serum and Chemonitor quality controls (containing CBZ without CBZ-E) were spiked with variable amounts of CBZ-E. The apparent CBZ levels were measured by PETINIA and EMIT 2000 methods. The interference from OCBZ and HCBZ was directly assessed by measuring the apparent CBZ levels in Chromsystems Trileptal quality controls (containing OCBZ and HCBZ). In the second part of the study, the CBZ levels of serum samples from 49 patients, including 2 patients with massive CBZ ingestion, were measured by immunoassays and compared with a high-pressure liquid chromatography (HPLC) reference technique allowing the simultaneous measurement of CBZ and CBZ-E. The antibody used in the PETINIA assay cross-reacts (about 90%) with CBZ-E. In one case of CBZ poisoning (CBZ and CBZ-E levels measured by HPLC were 26.2 and 18.2 mg/L, respectively), CBZ level measured by PETINIA was falsely elevated (42.5 mg/L). In contrast, the specificity of EMIT 2000 was satisfactory (29.5 mg/L). The two immunoassays tested showed low cross-reactivity with OCBZ and HCBZ. In conclusion, it appears that the CBZ-E metabolite present in samples can falsely increase CBZ levels measured by the PETINIA assay.
ISSN:0163-4356
出版商:OVID
年代:2003
数据来源: OVID
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7. |
Therapeutic Drug Monitoring of Olanzapine: The Combined Effect of Age, Gender, Smoking, and Comedication |
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Therapeutic Drug Monitoring,
Volume 25,
Issue 1,
2003,
Page 46-53
Marianne Gex-Fabry,
Androniki Balant-Gorgia,
Luc Balant,
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摘要:
Therapeutic drug monitoring (TDM) data for the antipsychotic drug olanzapine were investigated with respect to concentration versus dose relationship, intraindividual versus interindividual variability, and the combined influence of patient characteristics on steady-state concentration. The study included 250 patients, with daily doses ranging from 2.5 to 30 mg. Median concentration to dose ratio was 2.1 (ng/mL)/(mg/d), with 90% of the distribution in a fivefold range. In the first subgroup of patients with two measurements at different doses (n = 21), data were in keeping with linear concentration versus dose relationship. In the second subgroup of patients with repeated measurements at a constant daily dose (n = 40), estimates of within-patient and between-patient variabilities were 30.5% and 49.4%, respectively. In the whole sample, multiple regression analysis of dose-normalized concentration revealed significant effects of time postdose (−18% per 12 hours delay,P< 0.05), age ≥60 years (+27%,P< 0.005), cigarette smoking (−12%,P< 0.05), and comedication with fluvoxamine (+74%,P< 0.001), paroxetine, fluoxetine, or sertraline (considered together, +32%,P< 0.05), venlafaxine (+27%,P< 0.05), and inducers of P450 enzymes (−40%,P< 0.001). The final model included a tendency for higher concentration associated with female gender (+11%,P= 0.07) and accounted for 27% of observed interindividual variability. When considering a worst-case scenario, an elderly, nonsmoking woman prescribed fluvoxamine comedication was predicted to reach a 4.6-fold higher olanzapine concentration than a young male smoker coadministered carbamazepine. The current study suggests that patients characterized by a combination of factors associated with altered metabolism may benefit from olanzapine TDM.
ISSN:0163-4356
出版商:OVID
年代:2003
数据来源: OVID
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8. |
Plasma Gabapentin Concentrations in Children With Epilepsy: Influence of Age, Relationship With Dosage, and Preliminary Observations on Correlation With Clinical Response |
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Therapeutic Drug Monitoring,
Volume 25,
Issue 1,
2003,
Page 54-60
Giuliana Gatti,
Anna Ferrari,
Renzo Guerrini,
Paolo Bonanni,
Ilaria Bonomi,
Emilio Perucca,
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摘要:
The influence of age and administered daily dosage on the plasma concentrations of gabapentin (GBP) at steady state was evaluated in a group of 41 children and young adults (aged 3–30 years) receiving long-term adjunctive treatment with GBP for the management of refractory partial-onset seizures. For each patient, peak and trough concentrations were determined by a specific high-performance liquid chromatography (HPLC) method in samples obtained before the morning dose and 2.5 hours later, respectively. To assess within-subject relationship between plasma concentration and dosage, 30 patients were evaluated at more than one dosage level. Within the assessed dose range, plasma GBP concentrations were linearly related to dose. Apparent oral clearance values (mean ± SD) in children aged 6 years or less (4.8 ± 0.9 mL/kg/min) were comparable with those observed in children aged 7 to 15 years (4.6 + 1.5 mL/kg/min) and moderately higher than those found in young adults (3.9 + 0.9 mL/kg/min), even though differences among groups failed to reach statistical significance. There was, however, a significant difference in CL/F between children aged 10 years or less and older children (5.1 ± 1.1 vs. 3.8 ± 1.2 mL/kg/min,P< 0.005). Of the 41 patients who entered the study, 22 discontinued treatment, mostly due to insufficient efficacy. No significant difference in plasma GBP concentration was detected between patients showing a greater than 50% reduction in seizure frequency (4.1 ± 1.9 &mgr;g/mL, n = 11, mean ± SD) and those having no significant clinical improvement (4.4 ± 1.7 &mgr;g/mL, n = 30). These results indicate that in children given dosages up to 50 mg/kg/d (mean, 25 mg/kg/d), GBP pharmacokinetic analyses show no important deviation from linearity. The data also suggest that, on average, children may need moderately higher dosages to reach plasma GBP concentrations comparable with those found in adults. There seems to be a large variation in the plasma concentrations of the drug associated with a favorable therapeutic response.
ISSN:0163-4356
出版商:OVID
年代:2003
数据来源: OVID
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9. |
Correlation of Levetiracetam Concentrations Between Serum and Saliva |
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Therapeutic Drug Monitoring,
Volume 25,
Issue 1,
2003,
Page 61-66
Shellee Grim,
Melody Ryan,
Michael Miles,
Peter Tang,
Richard Strawsburg,
Ton deGrauw,
Toufic Fakhoury,
Robert Baumann,
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摘要:
PurposeMore than 100 drugs have been evaluated for salivary therapeutic drug monitoring since the 1970s. The most studied drugs are the anticonvulsants phenytoin, phenobarbital, and carbamazepine, demonstrating strong correlations between serum and saliva concentrations. No published data exist for levetiracetam (LEV) to the authors' knowledge. This study's objective is to determine the correlation between LEV serum and saliva concentrations.MethodsInvestigators identified subjects seen in neurology clinics at the University of Kentucky. Patients were eligible if they agreed to participate in this study, were taking LEV for a minimum of 4 weeks, and if a serum LEV concentration had been ordered by their physician. Patients spit a minimum of 0.25 mL into a cup to obtain saliva samples. Blood samples were obtained by phlebotomy.ResultsSerum and saliva LEV concentrations were determined via high-performance liquid chromatography (HPLC) in two separate reference laboratories. Linear regression analysis was used to evaluate correlations. Serum and saliva samples were obtained from 40 patients (22 female, 18 male), ranging from 3 to 57 years of age. The mean ± SD serum LEV concentration for reference laboratory A was significantly lower (P< 0.0001) than reference laboratory B, 23.6 ± 13.8 &mgr;g/mL and 27.0 ± 16.9 &mgr;g/mL, respectively. The mean ± SD saliva to serum concentration fraction was also different for the two laboratories, i.e., 41.0% ± 0.15% for lab A and 36.0% ± 0.15% for lab B (P= 0.001). The correlation coefficients for the two laboratories were similar, 0.87 and 0.86 (bothP< 0.0001) for labs A and B, respectively.ConclusionA significant positive correlation exists between LEV saliva and serum concentrations. The ability to monitor LEV therapy using saliva may provide benefits that include facilitating sample collection and improving the quality of life for persons with epilepsy. Patients with poor venous access, such as children and elderly patients, and persons afraid of needles may particularly benefit from this method.
ISSN:0163-4356
出版商:OVID
年代:2003
数据来源: OVID
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10. |
Evaluation of Estimated and Measured Creatinine Clearances for Predicting the Pharmacokinetics of Vancomycin in Adult Liver Transplant Recipients |
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Therapeutic Drug Monitoring,
Volume 25,
Issue 1,
2003,
Page 67-72
David Taber,
Amy Fann,
Greg Malat,
Robert Dupuis,
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摘要:
This study examined the pharmacokinetics and dosing requirements of vancomycin in adult liver transplant recipients and also evaluated the predictability of determining vancomycin-dosing requirements utilizing an estimated creatinine clearance (CrCl) approach. Twenty adult liver transplant recipients were included in this analysis. Vancomycin pharmacokinetic parameters and dosing requirements calculated from estimated CrCl and population-based pharmacokinetic equations were compared with values calculated using serum concentrations and assuming a one-compartment model. Compared with the values obtained using equations to estimate the CrCl and vancomycin pharmacokinetics (t1/2, Cl, and Vd), the actual values were statistically different for half-life and clearance (11.0 vs. 16.4 hours and 52 vs. 36 mL/min, respectively;P< 0.01). Additionally, CrCl that were estimated using population-based formulas significantly overestimated actual CrCl calculated using 24-hour urine collections (65–78 vs. 43 mL/min;P< 0.05). The results from this study indicate that serum creatinine concentrations do not adequately predict glomerular filtration rates (GFR) or vancomycin clearance in adult liver transplant recipients. Based on these results, the use of 24-hour urine CrCl to predict GFR and serum concentrations to properly dose vancomycin is advocated.
ISSN:0163-4356
出版商:OVID
年代:2003
数据来源: OVID
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