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1. |
Introduction by New Reviews Editor |
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Therapeutic Drug Monitoring,
Volume 21,
Issue 1,
1999,
Page 1-1
David Holt,
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ISSN:0163-4356
出版商:OVID
年代:1999
数据来源: OVID
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2. |
Clinical Pharmacokinetics of Tacrolimus in Heart Transplant Recipients |
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Therapeutic Drug Monitoring,
Volume 21,
Issue 1,
1999,
Page 2-7
Mario Regazzi,
Mauro Rinaldi,
Mariadelfina Molinaro,
Carlo Pellegrini,
Monica Calvi,
Eloisa Arbustini,
Elena Bellotti,
Vanni Bascapè,
Luigi Martinelli,
Mario Viganò,
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摘要:
We report pharmacokinetic data on tacrolimus in 14 heart transplant patients (2 women, 12 men). The median age and the median body weight were 55.5 years (range, 23-61 years) and 67.0 kg (55-79 kg), respectively. All patients were maintained on a triple-drug protocol (tacrolimus, azathioprine, and prednisone), with a 7-day antithymocyte globuline induction. The first tacrolimus dose, administered orally 1 to 5 days posttransplant, ranged from 0.03 to 0.4 mg/kg (median = 0.052 mg/kg). The maintenance dose ranged from 0.03 to 0.13 mg/kg/day (administered in two equal doses) to achieve blood levels of 5 of 20 ng/ml, as determined by a microparticle enzyme immunoassay (MEIA). Whole blood samples were drawn just before, at 0.5 hour, and at 1, 2, 3, 4, 6, 8, 10, and 12 hours after the administration of the first dose; trough levels were measured thereafter. The mean oral clearance (CL/F) and apparent volume of distribution (Vd/F) averaged 0.21 ± 0.08 L/hour/kg and 2.4 ± 0.8 L/kg while the half-life averaged 8.7 ± 3.5 hours. Tacrolimus accumulation index during chronic therapy (Rac= Cminsteady state/Cminfirst dose, normalized to the same dose) averaged 1.3. Eighty-eight percent of the trough blood levels measured in our patients were within 5 and 20 ng/ml. The incidence of rejection in the study population was extremely low: a prevalence of grade 2 rejection or more, of 0.4 ± 0.8 episodes/patient was observed after a follow-up period of 8.8 ± 2.2 months. Only one patient experienced severe renal toxicity, probably because of his preoperative precarious hemodynamic status. Pharmacokinetic data suggest that maintenance tacrolimus daily dose should be equal to 0.1 mg/kg/day to obtain trough blood concentrations of ∼ 10 ng/ml. Inter- and intra-patient variability of tacrolimus blood concentration should be expected and justify careful monitoring.
ISSN:0163-4356
出版商:OVID
年代:1999
数据来源: OVID
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3. |
Cyclosporine Plasma Unbound Fraction in Heart and Lung Transplantation Recipients |
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Therapeutic Drug Monitoring,
Volume 21,
Issue 1,
1999,
Page 8-16
Fatemeh Akhlaghi,
John Ashley,
Anne Keogh,
Kenneth Brown,
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摘要:
To investigate the variability in the unbound fraction (fU) of cyclosporine in recipients of heart, heart-lung, and lung transplantation, cyclosporine fUwas derterminedex vivoin plasma by equilibrium dialysis. In a retrospective study, 260 samples of plasma (one to seven per patient) were obtained from 89 heart (86%), lung (9%), and heart-lung (5%) transplant patients. The unbound fraction (×100) of cyclosporine ranged from 0.52% to 3.94%, with an overall mean of 1.53% ± 0.375% (SD). The mean percentage unbound for individual patients ranged from 0.71% to 1.98%, giving a 2.8-fold interpatient variation. In heart transplant recipients (66 patients), the values of fUwere significantly lower (p< 0.01) during more severe rejection episodes, which required antirejection treatment (endomycardial biopsy result of grade 3a and higher) than in the absence of rejection (grade 0) or during grade 1a rejections. The value of fUdid not vary with organ transplanted (p= 0.35) or etiology of organ failure (p= 0.32). Cyclosporine fUwas negatively correlated with the age of the patient (r= -0.18,p< 0.05). Correlations were not observed between fUand blood biochemical and cytologic indices. However, fUwas significantly lower (p< 0.01) in hypercholesterolemic transplant recipients (1.37 ± 0.52%) than in normocholesterolemic patients (1.60 ± 0.63%). Administration of simvastatin resulted in a significant increase in the mean fUfrom 1.40 ± 0.09%) to 1.82 ± 0.13% (pairedttest, n = 13;p< 0.01). In patients who received ketoconazole, fUwas not different from controls. These findings suggest that the level of cyclosporine fUmay be an important determinant immunosuppressive activity of cyclosporine. Moreover, the variation in fUcould be strongly related to the concentration of serum lipoproteins; interpretation of the results of cyclosporine monitoring thus requires consideration of the lipidemic status of the patient.
ISSN:0163-4356
出版商:OVID
年代:1999
数据来源: OVID
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4. |
Randomized, Trough Blood Cyclosporine Concentration-controlled Trial to Compare the Pharmacodynamics of Sandimmune and Neoral in De Novo Lung Transplant Recipients |
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Therapeutic Drug Monitoring,
Volume 21,
Issue 1,
1999,
Page 17-26
Andrew Trull,
Louise Steel,
Linda Sharples,
Susan Stewart,
Jayan Parameshwar,
Keith McNeil,
John Wallwork,
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摘要:
The greater and more consistent absorption of cyclosporine from the microemulsion formulation (Neoral; Novartis Pharmaceuticals Ltd., Frimley, UK) when compared with that from the original form (Sandimmune; Novartis Pharmaceuticals Ltd., Frimley, UK) results in greater systemic exposure. Lung transplant recipients could particularly benefit from this enhanced exposure, but not at the expense of excessive cyclosporine toxicity. We compared the pharmacodynamics of Neoral and Sandimmune over the first postoperative year in 50 lung transplant recipients. Twenty-eight patients were randomly selected to receive Neoral and 22 to receive Sandimmune. Nine patients with cystic fibrosis (CF) were randomly selected independently (5, Neoral; 4, Sandimmune). Patients were maintained on similar trough blood cyclosporine concentrations (C0) throughout the 12-month follow-up. A limited blood sampling strategy was adopted to compare the pharmacokinetics of the two formulations at the end of weeks 1 to 4, and of weeks 13, 26, 39, 52. The influence of any difference between the pharmacokinetics of Neoral and Sandimmune on either efficacy or toxicity of the drug was investigated during the follow-up period. Patients in the Neoral and the Sandimmune groups were matched demographically. There were no differences in dose-normalized blood cyclosporine concentrations measured predose (C0) or 6 hours postdose between the two groups. However, the measurement at 2 hours postdose (C2) and the total AUC0-6were significantly greater in the Neoral group in both CF and non-CF patients at all visits (p< 0.001). Non-CF patients required 9% lower doses of Neoral to achieve comparable C0measurements to those patients receiving Sandimmune. However, patients with CF required 2 to 3 times the dose of both Neoral and Sandimmune to achieve the same C0as non-CF patients. The linear rejection rate in the Sandimmune group was 1.87 episodes per patient year, which was similar to the rejection rate of 1.97 episodes per patient year in the Neoral group. Serial lung function, blood biochemistry and hematology, mortality and the incidence of severe renal dysfunction, hypertension, infection, seizures, and new-onset diabetes were all similar in the two groups. Despite equivalent C0, those in the Neoral group were consistently exposed to greater blood cyclosporine concentrations during the dosing interval than those in the Sandimmune group. This did not increase the incidence of serious cyclosporine-associated side effects or influence the rate of acute rejection either. When data from the Neoral and Sandimmune groups were combined, measurements of C0but not C2or C6were associated with the risk of acute lung allograft rejection.
ISSN:0163-4356
出版商:OVID
年代:1999
数据来源: OVID
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5. |
Abbreviated Pharmacokinetic Profiles in Area-Under-the-Curve Monitoring of Cyclosporine Therapy in De Novo Renal Transplant Patients Treated with Sandimmune or Neoral |
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Therapeutic Drug Monitoring,
Volume 21,
Issue 1,
1999,
Page 27-34
Christopher Marsh,
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摘要:
Trough cyclosporine (CsA) blood levels obtained just before administration of the next dose are monitored to guide dosage adjustments. However, these levels may not be the best indicator of total drug exposure. In a study of de novo renal transplant patients, pharmacokinetic profiles of CsA after administration of the traditional CsA formulation (Sandimmune [CsA-SIM] Novartis, E. Hanover, NJ) or the new formulation, cyclosporine capsules for microemulsion (Neoral [CsA-ME] Novartis, E. Hanover, NJ), were compared at 1, 4, 8, and 12 weeks posttransplantation under fasting and fed conditions. The data were analyzed to assess the degree of correlation between total drug exposure, indicated by the area under the concentration-versus-time curve at the end of a 12-hour dosing interval (AUC12h), and drug exposure calculated from concentrations obtained at different time points (abbreviated AUC [AAUC]). With AAUCs calculated from trough levels and levels at 4 hours postdose, the average degree of correlation with AUC12hwasr= 0.915 for CsA-ME andr= 0.853 for CsA-SIM. The degree of correlation was smaller with CsA-SIM and additional sampling times may be required. With CsA-ME, these two sampling time points appear to provide a reliable indication of total CsA exposure; CsA-ME may thus provide advantages in terms of blood level monitoring and patient management.
ISSN:0163-4356
出版商:OVID
年代:1999
数据来源: OVID
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6. |
Evidence That Tacrolimus Augments the Bioavailability of Mycophenolate Mofetil Through the Inhibition of Mycophenolic Acid Glucuronidation |
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Therapeutic Drug Monitoring,
Volume 21,
Issue 1,
1999,
Page 35-43
Keith Zucker,
Alexandra Tsaroucha,
Les Olson,
Violet Esquenazi,
Andreas Tzakis,
Joshua Miller,
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摘要:
We previously reported an unexpected augmentation of mycophenolic acid (MPA) levels (trough and AUC0-12) in patients receiving mycophenolate mofetil (MMF) in combination with tacrolimus versus patients receiving the same dose of MMF in combination with cyclosporin A (CsA). This finding was accompanied by a corresponding reduction of the inactive glucuronide metabolite of MPA (MPAG) in patients, suggesting that tacrolimus may effect the conversion of MPA to MPAG by the enzyme UDP-glucuronosyltransferase (UDPGT). To investigate this possibility directly, UDPGT was extracted from human liver and kidney tissue and its activity was characterized using MPA as a substratein vitro, assessing the conversion of MPA to MPAG using analysis by high-performance liquid chromatography. With crude microsomal preparations, amounts of UDPGT at least 100 times higher in specific activity (i.e., units to milligrams of protein) could be extracted per gram of tissue from kidney as opposed to liver. This result did not appear to be related to the coextraction of a liver-specific UDPGT inhibitor because initial enzyme kinetic values (Vmaxandkm) were identical for kidney and liver extracts, and further purification of the liver enzyme did not enhance activity (as is seen when inhibitors are removed during purification). With further UDPGT purification (∼200-fold) from kidney extracts using a combination of ammonium sulfate precipitation, followed by anion exchange, hydroxyapatite, and size exclusion chromatography, the enzyme was more than 80% pure when assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Initial enzyme kinetic analysis of this purified product showed akmvalue for MPA of 35.4 ± 5.7 µg/mL and a Vmaxof 2.87 ± 0.31 MPAG produced per hour (n = 7). The addition of clinically relevant concentrations of CsA (200-1,000 ng/mL) or tacrolimus (10-25 ng/mL) resulted in a dose-dependent inhibition of the UDPGT enzyme by both agents with tacrolimus, which was approximately 60-fold more efficient as an inhibitor. The calculated inhibition constants (KI) of tacrolimus and CsA for the purified UDPGT were 27.3 ± 5.6 ng/ml and 2,518 ± 1473 ng/ml, respectively. Both agents displayed an inhibition profile characteristic of a competitive inhibitor (substrate) that could be demonstrated in a reciprocal experiment with CsA as a substrate, but not with tacrolimus. This finding suggested that the significantly more efficient inhibition of UDPGT by tacrolimus may occur by a more complicated mechanism that is yet to be determined.
ISSN:0163-4356
出版商:OVID
年代:1999
数据来源: OVID
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7. |
Correlation Between Pretransplantation Test Dose Cyclosporine Pharmacokinetic Profiles and Posttransplantation Sirolimus Blood Levels in Renal Transplant Recipients |
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Therapeutic Drug Monitoring,
Volume 21,
Issue 1,
1999,
Page 44-49
Bruce Kaplan,
Herwig-Ulf Meier-Kriesche,
Kimberly Napoli,
Barry Kahan,
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摘要:
We sought to determine whether pretransplantation test dose pharmacokinetic measurements of cyclosporine (CsA) concentrations would forecast the posttransplantation blood concentrations of sirolimus in renal transplant patients treated de novo with CsA, sirolimus, and prednisone. All 44 renal transplant recipients enrolled in Phase I/II studies of de novo posttransplantation therapy with sirolimus, CsA, and prednisone underwent pretransplantation pharmacokinetic profiling after having received paired intravenous (IV) and oral test doses of CsA. After transplantation, all patients were treated with CsA on a once- or twice-daily schedule (according to a concentration-controlled regimen), with tapering doses of prednisone, and with fixed doses of sirolimus on a once-daily schedule. Patients were divided into four cohorts based on the deviation of their pretransplantation CsA clearance or bioavailability values from the mean. Patients with high pretransplantation CsA clearance rates displayed a significantly lower mean posttransplantation value of sirolimus trough concentrations than patients with low pretransplantation CsA clearance rates. In contrast, values for pretransplantation absolute oral CsA bioavailability failed to correlate with the mean posttransplantation concentration of sirolimus but did predict posttransplantation CsA bioavailability. Therefore, pretransplantation CsA clearance rate estimates may forecast posttransplantation sirolimus concentrations, possibly guiding use of sirolimus therapy to achieve an optimal ratio of concentration-dependent immunosuppressive versus toxic effects.
ISSN:0163-4356
出版商:OVID
年代:1999
数据来源: OVID
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8. |
Prediction of Tacrolimus Blood Levels by Using the Neural Network with Genetic Algorithm in Liver Transplantation Patients |
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Therapeutic Drug Monitoring,
Volume 21,
Issue 1,
1999,
Page 50-56
Hsiang-Yin Chen,
Ta-Cheng Chen,
David Min,
Gary Fischer,
You-Min Wu,
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摘要:
The neural network (NN) is a technique using an artificial intelligent concept in predicting outcomes by using various input variables. Tacrolimus pharmacokinetics has wide inter- and intra-subject variability and it is often difficult to predict its blood concentrations by dose alone. The objectives of this study are to select the clinically significant variables and to predict the blood concentration of tacrolimus in liver transplant patients by NN combined with genetic algorithm (GA). A total of thirty-two adult liver transplant patients from the University of Iowa Hospitals and Clinics were selected and the patients' data were retrospectively collected. These patient were randomly assigned into two groups: either the training group (n = 10), or testing group (n = 22). A back propagation (BP) NN was developed which contained two hidden layers. A dynamic BP NN based on the time series concept was trained by using the current and previous data sets to predict the trough levels of tacrolimus. The mean of the NN prediction for tacrolimus blood levels was not significantly different from the observed value by a paired t-test comparison (12.05 ± 2.67 ng/ml vs. 12.14 ± 2.64 ng/ml, p = 0.80). The average difference of the testing sets between the observed and predicted levels was 1.74 ng/ml with a range from 0.08 to 5.26 ng/ml which is clinically acceptable range. Thirty-seven out of 44 data sets (84%) in the testing group were within 3.0 ng/ml of the observed values. This study demonstrated that tacrolimus blood concentrations are precisely predictable in liver transplant patients using patients variables by NN.
ISSN:0163-4356
出版商:OVID
年代:1999
数据来源: OVID
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9. |
Factors Influencing the Population Pharmacokinetic Parameters of Phenytoin in Adult Epileptic Patients in South Africa |
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Therapeutic Drug Monitoring,
Volume 21,
Issue 1,
1999,
Page 57-62
Praneet Valodia,
Michael Seymour,
Raymond Miller,
Margaret McFadyen,
Peter Folb,
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摘要:
The influence of various covariates (including weight, race, smoking, gender, age, mild-to-moderate alcohol intake, and body surface area) on the population pharmacokinetic parameters of phenytoin in adult epileptic patients in South Africa was investigated. The parameters were the maximum metabolic rate (Vm) and the Michaelis-Menten (MM) constant (Km) of phenytoin. The study population comprised 332 black and colored epileptic patients (note: "black" refers to indigenous people of South Africa, who speak one of the Bantu languages as their native language; "colored" refers to people considered to be of mixed race, classified as such by the apartheid former government of South Africa). The influence of covariates on Vm and Km estimates was determined using nonlinear mixed-effects modeling (NONMEM). Parameter models describing the factors that could potentially influence Vm and Km were tested using the Michaelis-Menten parallel MM and first-order elimination models, to which 853 steady state dose-to-serum concentration pairs were fitted. The results indicated that body weight, smoking, race, and age (65 years or older), in descending order of importance, significantly influenced Vm (p< 0.05). Although a significant difference (p= 0.03) in Km was found between black and colored patients, incorporating the influence of race in Km in the final regression model did not improve the fit of the model to the data, which indicated that the variability in Km was accounted for by Vm. The scaling factors for smoking, colored patients and age (65 years or older) in Vm were 1.16, 1.10, and 0.88, respectively. These factors should be taken into account when adjusting phenytoin dose.
ISSN:0163-4356
出版商:OVID
年代:1999
数据来源: OVID
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10. |
Impact of Goal-Oriented and Model-Based Clinical Pharmacokinetic Dosing of Aminoglycosides on Clinical Outcome: A Cost-Effectiveness Analysis |
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Therapeutic Drug Monitoring,
Volume 21,
Issue 1,
1999,
Page 63-73
Nicolette A. E. M. van Lent-Evers,
Ron A. A. Mathôt,
William Geus,
Ben van Hout,
Alexander A. T. M. M. Vinks,
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摘要:
The benefits of a pharmacy-based, active therapeutic drug monitoring (TDM) service (ATM) on outcomes were examined in a prospective study at four hospitals. ATM involved pharmacokinetic dosage optimization at the start of treatment, subsequent Bayesian adaptive control, and frequent patient evaluation. Cost-effectiveness was calculated based on real costs. The ATM group comprised 105 patients and 127 patients with nonguided TDM who were followed up as controls. Forty-eight of the ATM and 62 of the nonguided TDM patients had an infection on admission. Peak concentrations in ATM patients were significantly higher (10.6 ± 2.9 mg/L; nonguided TDM, 7.6 ± 2.2 mg/L;p< 0.01). Trough levels in the ATM group were significantly lower (p< 0.01). There was a trend toward lower mortality in the ATM group (nine of 105 versus 18 of 127;p= 0.26) that was significant for patients with an infection on admission (one of the 48 ATM patients died versus nine of the 62 nonguided TDM patients;p= 0.023). ATM reduced the length of hospital stay for all patients in the study (20.0 ± 1.4 days; nonguided TDM, 26.3 ± 2.9 days;p= 0.045) and for patients admitted with an infection (12.6 ± 0.8 days; nonguided TDM, 18.0 ± 1.4;p< 0.001). The incidence of nephrotoxicity was reduced from 13.4% (nonguided TDM) to 2.9% (p< 0.01). With ATM, total costs were lower for all patients (Dutch guilders [DFL], 13,125 ± 9,267; nonguided TDM, DFL 16,862 ± 17,721;p< 0.05) and for patients admitted with an infection (DFL 8,883 ± 3,778; nonguided TDM, DFL 11,743 ± 7,437;p< 0.01). Goal-oriented, model-based dosing of aminoglycosides resulted in higher antibiotic efficacy, shorter hospitalization, and reduced incidence of nephrotoxicity. By combining efficacy with savings, ATM offered a significant alternative to usual care.
ISSN:0163-4356
出版商:OVID
年代:1999
数据来源: OVID
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