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1. |
International Association of Therapeutic Drug Monitoring and Clinical Toxicology: Newsletter |
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Therapeutic Drug Monitoring,
Volume 18,
Issue 1,
1996,
Page 0-0
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ISSN:0163-4356
出版商:OVID
年代:1996
数据来源: OVID
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2. |
Clonazepam Disposition in Pediatric Patients |
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Therapeutic Drug Monitoring,
Volume 18,
Issue 1,
1996,
Page 1-5
Walson Philip,
Edge James,
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摘要:
SummaryPlasma clonazepam (CZP) and its metabolite [7-aminoclonazepam (7ACZP) and 7-acetamidoclonazepam (7AACZP)] concentrations were measured during a single dosing interval in 10 pediatric epilepsy patients (2-18 years, 11-102 kg) who had been receiving CZP therapeutically from 2 weeks to 4 years. These concentrations were used to determine CZP and metabolite pharmacokinetics. With controlled dosing and postdose sample collection times, large variations were observed in calculated CZP nitroreduction rates [clearance (CL/F) ranged from 7 to 64 ml/h/kg] as well as 7ACZP acetylation rates (CL/Ffrom 10 to 85 ml/h/kg). No 7AACZP (i.e., <5 ng/ml) was detected by the methods used. Acetylation rates are known to be under genetic control. Further studies are needed to determine whether nitroreduction rates are also under genetic control and whether differences in either of these metabolic rates can explain intraindividual differences in clinical responses observed in CZP-treated patients.
ISSN:0163-4356
出版商:OVID
年代:1996
数据来源: OVID
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3. |
The Effects of Obesity on the Pharmacokinetics and Pharmacodynamics of Glipizide in Patients with Non-Insulin-Dependent Diabetes Mellitus |
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Therapeutic Drug Monitoring,
Volume 18,
Issue 1,
1996,
Page 6-13
Jaber Linda,
Ducharme* Murray,
Halapy Henry,
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摘要:
SummaryThe pharmacokinetics and pharmacodynamics of glipizide were evaluated in 20 patients with non-insulin-dependent diabetes mellitus (NIDDM). The group consisted of 12 obese subjects (seven women, five men; mean ± SD age, 53.5 ± 8.5 years; total body weight (TBW), 95.5 ± 17.2 kg; percentage >IBW (ideal body weight), 57.8 ± 31.7%); and eight nonobese subjects (two women, six men; age, 57.8 ± 11.7 years; TBW, 80.8 ± 9.9 kg; percentage >IBW, 15.6 ± 10.3%). After a 2-week antidiabetic drug-free period, patients were started on glipizide therapy for 12 weeks. Glipizide dosages were titrated to achieve specified therapeutic goals or a maximum daily dose of 40 mg. Glipizide pharmacokinetics were assessed by serum concentrations obtained during a 24-h pharmacokinetic evaluation performed after the first 5-mg dose (SD) and after 12 weeks of chronic therapy (CD). Glipizide pharmacodynamics were evaluated with serum glucose, insulin, and C-peptide responses to Sustacal tolerance test done at baseline, after SD, and after CD. No statistically significant differences in the SD pharmacokinetic parameters (Tmax = 3.1 ± 1.2 vs. 2.8 ± 1.6 h;Cmax = 332.5 ± 92.5 vs. 420.8 ± 142 g/L; area under the curve extrapolated to infinity (AUCI) = 2,598.3 ± 1,148 vs. 3,138.9 ± 1,847 g/h/L; oral clearance/bioavailability (CL/F), 2.3 ± 1.0 vs. 2.0 ± 1.0 L/h; volume of distribution/bioavailability (V/F), 19.5 ± 4.4 vs. 17.2 ± 4.3 L;t1/2 = 5.0 ± 2.3 vs. 5.2 ± 2.0 h) were observed between the obese and nonobese groups, respectively. The pharmacokinetic parameters assessed under CD conditions were also closely matched in the two groups. No differences in glucose responses to Sustacal challenge at baseline, SD, and CD (AUCO → 4.glucose: baseline, 52.3 ± 18.0 vs. 44.9 ± 9.8; SD, 50.4 ± 20.9 vs. 36.1 ± 11.0; CD, 37.8 ± 10.7 vs. 36.6 ± 8.5 mM/h) were noted between the obese and nonobese groups, respectively. However, glucose concentrations increased more and decreased to a smaller extent after SD in the obese as compared to nonobese subjects. Mean fasting serum insulin and C-peptide concentrations were not statistically different between the two groups. However, obese subjects exhibited higher fasting insulin (114.0 ± 69 vs. 68.8 ± 52 pM) at week 12 evaluation and C-peptide concentrations (0.83 ± 0.2 vs. 0.63 ± 0.2 nM) after SD as compared to the nonobese group. A smaller percentage increase in C peptide in response to Sustacal challenge was observed in the obese compared to the nonobese subjects (baseline, 60 ± 25 vs. 117 ± 117; SD, 119 ± 39 vs. 193 ± 149; and CD, 97 ± 56 vs. 163 ± 67%). In summary, the influence of obesity on glipizide pharmacokinetics appeared to be of little clinical significance. The observed differences in pharmacodynamics require further evaluation.
ISSN:0163-4356
出版商:OVID
年代:1996
数据来源: OVID
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4. |
Monitoring Free Extracellular Valproic Acid by Microdialysis in Epileptic Patients |
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Therapeutic Drug Monitoring,
Volume 18,
Issue 1,
1996,
Page 14-18
Ståhle*† Lars,
Alm* Christina,
Ekquist* Brita,
Lundquist* Birgitta,
Tomson‡ Torbjörn,
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摘要:
SummaryThis report describes the first experiences with monitoring of valproic acid pharmacokinetics in patients with epilepsy by subcutaneous microdialysis. We could demonstrate good correspondence between total concentration in plasma and free concentration in plasma and dialysate. In this study the dialysate concentrations were not corrected for in vivo recovery because the aim was to explore the possibilities of the method in routine clinical work rather than to estimate absolute concentrations in extracellular fluid. In one patient, microdialysis was continued for 3 days without problems. The dialysis probe with a small portable pump could be carried without any notable interference with daily activities of patients in the ward. No side effects were noted. The results encourage further studies along two lines: to investigate the free-concentration effect relation for valproic acid and to monitor drug concentration under nonhospital conditions in order to study the interaction between daily activities and drug concentration.
ISSN:0163-4356
出版商:OVID
年代:1996
数据来源: OVID
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5. |
The Effect of Age on the Apparent Clearance of Felbamate: A Retrospective Analysis Using Nonlinear Mixed-Effects Modeling |
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Therapeutic Drug Monitoring,
Volume 18,
Issue 1,
1996,
Page 19-29
Banfield* Christopher,
Zhu† Guang-Rui,
Jen† J.,
Jensen‡ Peder,
Schumaker§ Robert,
Perhach§ James,
Affrime* Melton,
Glue* Paul,
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摘要:
SummaryThe effects of age on felbamate apparent clearance were examined through a retrospective analysis of plasma concentration data from 700 pediatric and adult epileptic patients (age range, 2-74 years) enrolled in six clinical studies. Patients received felbamate as monotherapy or in combination with either the antiepileptic drugs (AEDs) carbamazepine (CBZ), phenytoin (PHT), or valproate (VPA). Data were analyzed using a nonlinear mixed-effects pharmacostatistical modeling technique (NONMEM). Factors in the model included age, body weight, and concomitant AEDs. Apparent clearance was highest in the very young and decreased during the early teenage years, with minimal changes observed beyond 13 years. Mean apparent clearance values were ≈40% higher in children (2-12 years) compared with those in adults (13-65 years). This pattern and its magnitude were consistent whether felbamate was administered alone or coadministered with CBZ, PHT, or VPA. The increase in clearance is minimal compared with other AEDs including PHT, CBZ, and phenobarbital. Enzyme-inducing AEDs (CBZ and PHT) increased felbamate apparent clearance by 32-38% relative to monotherapy, whereas coadministration with VPA had a minimal effect on felbamate apparent clearance. Dose/concentration linearity was observed at all ages during mono- or polytherapy. These findings suggest that felbamate dosing should be relatively uncomplicated in children relative to that in adults.
ISSN:0163-4356
出版商:OVID
年代:1996
数据来源: OVID
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6. |
Relationship Between Plasma and Saliva Quinine Levels in Humans |
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Therapeutic Drug Monitoring,
Volume 18,
Issue 1,
1996,
Page 30-33
Babalola Chinedum,
Bolaji Oluseye,
Ogunbona Festus,
Dixon* Patrick,
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摘要:
SummaryThe relationship between saliva and plasma levels of quinine was studied in four healthy volunteers. After a single oral dose of quinine sulfate (600 mg) to the volunteers, quinine was determined in both saliva and plasma simultaneously over a 48-h period by an ion pair reverse-phase high performance liquid chromatography method. Thetmax(4.3 ± 0.5 h) and elimination half-life (11.8 ± 2.9 h) of quinine derived from saliva levels were comparable with those obtained from plasma levels (tmax= 2.8 ± 0.2 h,t½= 12.9 ± 2.3 h). A significant correlation existed between the plasma and saliva concentrations of the drug (r= 0.93, n = 20, p < 0.001). The mean saliva/plasma quinine concentration ratio was 0.24 ± 0.02. The results suggest that quinine is passively secreted into saliva and that saliva level determination may be useful as a noninvasive method in the evaluation of pharmacokinetic parameters and therapeutic drug monitoring of quinine.
ISSN:0163-4356
出版商:OVID
年代:1996
数据来源: OVID
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7. |
Estimating Concentrations of Total Digoxin and Digoxin-Like Immunoreactive Substances in Volume-Expanded Patients Being Treated with Digoxin |
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Therapeutic Drug Monitoring,
Volume 18,
Issue 1,
1996,
Page 34-39
Dasgupta Amitava,
Schammel David,
Limmany Anicia,
Datta Pradip,
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摘要:
SummaryHigh concentrations of digoxin-like immunoreactive substances (DLIS) artificially increase serum digoxin concentrations. However, DLIS are absent in the protein-free ultrafiltrate because of their strong binding with serum macromolecules, whereas ≈75% of digoxin can be found in the ultrafiltrate. Using regression analysis, we devised equations by which total digoxin concentration can be calculated from free digoxin and albumin concentrations in serum. We used two different assays, fluorescence polarization and chemiluminescence, for measuring total and free-digoxin concentrations in sera. Both equations were very similar. Because measured concentrations of digoxin in the serum exhibit DLIS interferences, the measured concentrations were sometimes higher in volume-expanded patients than the calculated digoxin concentrations. We also estimated the extent of interferences from DLIS by subtracting the calculated digoxin concentration from the measured digoxin concentration in volume-expanded patients.
ISSN:0163-4356
出版商:OVID
年代:1996
数据来源: OVID
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8. |
Steady-State Plasma Concentrations of Diltiazem and Its Metabolites in Patients and Healthy Volunteers |
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Therapeutic Drug Monitoring,
Volume 18,
Issue 1,
1996,
Page 40-45
Yeung Pollen,
Buckley Susan,
Hung Orlando,
Pollak P.,
Barclay Katherine,
Feng Joe,
Farmer Patrick,
Klassen Gerald,
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摘要:
SummaryDiltiazem (DTZ) is a calcium antagonist widely used in the treatment of angina and hypertension. It is extensively metabolized in humans via N-demethylation, O-demethylation, deacetylation, and oxidative deamination, yielding a host of metabolities, some of which have potent pharmacological properties. After our initial identification of O-desmethyl DTZ (Mx) and N,O-didesmethyl DTZ (MB) as major metabolites of DTZ and our subsequent of identification of their chemical synthesis, an improved high-performance liquid chromatography assay was developed to determine the plasma concentrations of DTZ and seven of its major basic metabolites, including the previously unquantitated Mx and MB. The system consisted of a C18analytical column protected by a C18cartridge guard column and a variable wavelength ultraviolet detector set at 237 nm. The mobile phase was a mixture of methanol, 0.04Mammonium acetate, and acetonitrile (38:36:26) containing 0.08% triethylamine, with final pH of the mobile phase adjusted to 7.5. The system was operated at room temperature isocratically at a flow rate of 1.2 ml/min. Using verapamil as an internal standard, DTZ and the basic metabolites in plasma were determined in young healthy volunteers (n = 21) and in patients with ischemic heart disease (n = 19) at steady state after repeated oral doses of 60 mg DTZ four times daily. Preliminary results show that steady-state plasma concentrations of DTZ and its metabolites were higher in the older patients than in young healthy subjects (p < 0.05).
ISSN:0163-4356
出版商:OVID
年代:1996
数据来源: OVID
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9. |
Mixed-Effect Modeling for Detection and Evaluation of Drug Interactions: Digoxin-Quinidine and Digoxin-Verapamil Combinations |
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Therapeutic Drug Monitoring,
Volume 18,
Issue 1,
1996,
Page 46-52
Bauer Larry,
Horn John,
Pettit Herbert,
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摘要:
SummaryMixed-effect modeling has been suggested as a possible tool to detect and describe drug interactions in patient populations receiving drug combinations for the treatment of disease states. The mixed-effect modeling program, NONMEM, was used to measure the effects of the well-known digoxin-quinidine and digoxin-verapamil drug interactions in 294 patients receiving oral digoxin as hospital inpatients. Fourteen percent of the population took either quinidine or verapamil concurrently with digoxin (mean quinidine dose = 857 ± 397 mg/day, verapamil = 261 ± 110 mg/day). Two regression models for digoxin oral clearance were used. Model 1 used the knowledge that digoxin is eliminated by both renal and nonrenal routes (TVCL = ClNR+m· CrCl, where TVCL is the population digoxin oral clearance, ClNRis the nonrenal clearance, andmis the slope of the line that relates creatinine clearance (CrCl) to digoxin clearance); model 2 used a more conventional regression approach with a simple series of multipliers. For both models, quinidine administration decreased population digoxin oral clearance by ≈45% and verapamil therapy decreased population digoxin oral clearance by ≈30%. These values are similar to those found by traditional drug interaction studies conducted in small patient or normal subject populations. Mixed-effect modeling can detect clinically relevant drug interactions and produce information similar to that found in traditional pharmacokinetic crossover study designs.
ISSN:0163-4356
出版商:OVID
年代:1996
数据来源: OVID
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10. |
Extreme Values of the Concentration/Dose Ratio as a Risk Factor of Obtaining Suboptimal Nortriptyline Serum Concentrations |
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Therapeutic Drug Monitoring,
Volume 18,
Issue 1,
1996,
Page 53-59
Linnet Kristian,
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摘要:
SummaryUsing nortriptyline as an example of a typical tricyclic antidepressant, I studied the relation between the steady-state concentration/dose ratio (C/D) and the performance of therapeutic drug monitoring (TDM), with a focus on the frequency of serum concentrations located in the therapeutic interval. A TDM database comprising 1,214 patients, of whom 619 patients had more than one sample taken, was used. The median C/D value for the patients was 4.05 [nM]/mg with 5th and 95th percentiles of 1.80 and 9.60, respectively. A total of 18.6% of the patients with C/D values below the 5th percentile had serum concentrations in the therapeutic interval at the first occasion, increasing to 49% for the average of the succeeding samples. These values were lower than those for the total group, 60.4 and 68.9%, respectively. For those with C/D values exceeding the 95th percentile, 36.2% had initial serum concentrations in the therapeutic interval, increasing to 66.3% for the average of succeeding samples. Only 11 patients (0.9%) had very high initial serum concentrations (>1,200 nM). Thus patients with low C/D values are at risk of being underdosed, even after successive samples, whereas adequate dose correction is more likely to be implemented for those with average or high C/D values. Saturation kinetics for those with low C/D values was not a problem of clinical significance. Neither was lack of steady-state at the first occasion a problem for those with high C/D values (suspected poor metabolizers).
ISSN:0163-4356
出版商:OVID
年代:1996
数据来源: OVID
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