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1. |
The 10,11‐Epoxide‐10,11‐diol Pathway of Carbamazepine in Early Pregnancy in Maternal Serum, Urine, and Amniotic FluidEffect of Dose, Comedication, and Relation to Outcome of Pregnancy |
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Therapeutic Drug Monitoring,
Volume 15,
Issue 1,
1993,
Page 1-10
Juliette Omtzigt,
Frans Los,
Jaap Meijer,
Dick Lindhout,
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摘要:
Epoxide metabolites of carbamazepine (CBZ) have been suggested to play a role in the occurrence of congenital malformations observed in infants exposed to CBZ. We have investigated the 10,11-epoxide-10,11-diol pathway of CBZ in pregnant epileptic patients receiving CBZ alone or in combination with other antiepileptic drugs in relation to the outcome of pregnancy in a prospective manner. The women were referred to our clinic before 16 weeks of gestation for prenatal diagnosis of fetal malformations, including neural tube defects, by ultrasound and amniocentesis. The availability of amniotic fluid samples enabled us to determine to what extent CBZ and its main metabolites reached the amniotic fluid. In 100 pregnancies with first trimester CBZ exposure (including 7 with malformed outcome), parent drug and metabolite concentrations in maternal serum were evaluated. CBZ-10,11-epoxide concentrations increased with increasing dose. Comedication with phenobarbital led to lower 10,11-epoxide concentrations in maternal serum and a higher percentage of the dose recovered in urine as 10,11-diol. Valproate comedication led to slightly higher 10,11-epoxide concentrations in maternal serum, in combination with lower CBZ concentrations and a lower percentage of the dose recovered in the urine as 10,11-diol, in amniotic fluid, concentrations of CBZ and its main metabolites in most patients were 2 to 2.5 times higher than the free concentrations in maternal serum. Metabolites and parent drug concentrations in amniotic fluid correlated with their free concentration in maternal serum, but stronger with each other in amniotic fluid. No significant differences in levels of CBZ and its metabolites were observed between pregnancies with normal and malformed outcome.
ISSN:0163-4356
出版商:OVID
年代:1993
数据来源: OVID
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2. |
Pharmacokinetics of Citalopram in Relation to the Sparteine and the Mephenytoin Oxidation Polymorphisms |
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Therapeutic Drug Monitoring,
Volume 15,
Issue 1,
1993,
Page 11-17
S. Sindrup,
K. Brøsen,
M. Hansen,
T. Aaes-Jørgensen,
K. Overø,
L. Gram,
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摘要:
The relationship between the metabolism of the selective serotonin reuptake inhibitor citalopram and the sparteine and mephenytoin oxidation polymorphisms was studied in 24 healthy male volunteers, constituting panels of extensive metabolizers of sparteine and mephenytoin (n = 10), poor metabolizers of sparteine (n = 8), and poor metabolizers of mephenytoin (n = 6). Each subject was given 40 mg/day citalopram for 10 days and citalopram, and its des- and didesmethylmetabolites were assayed in serum and urine. Using a nonenantioselective analytical method (high-performance liquid chromatography), it was shown that the citalopram elimination partially depends on the mephenytoin oxygenase, since steady-state serum concentration, half-life, and area under the serum concentration/time curve for citalopram were significantly higher in poor metabolizers of mephenytoin than in extensive metabolizers of mephenytoin. Both citalopram total clearance and demethylation clearance (formation of desmethylcitalopram) were significantly lower in poor metabolizers of mephenytoin compared to extensive metabolizers (median 15.2 vs. 27.3 and 2.6 vs. 5.9 L/h, respectively). It was further indicated that the demethylation of desmethylcitalopram to didesmethylcitalopram depends on the sparteine oxygenase CYP2D6. Didesmethylcitalopram could virtually not be detected in any poor metabolizers of sparteine, contrasting measurable serum levels in all sparteine/mephenytoin extensive metabolizers. The demethylation clearance of desmethylcitalopram was significantly lower in sparteine poor metabolizers compared to extensive metabolizers (0.3 vs. 2.4 L/h, respectively). During administration of citalopram, there was a modest increase in sparteine metabolic ratio from median 0.31 to 0.80 in extensive metabolizers of sparteine, whereas the mephenytoinS/Rratio was unaltered during citalopram treatment. Both the sparteine and the mephenytoin oxidation polymorphism thus appear to contribute partially to the total pharmacokinetic variability of citalopram.
ISSN:0163-4356
出版商:OVID
年代:1993
数据来源: OVID
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3. |
CitalopramInteraction Studies with Levomepromazine, Imipramine, and Lithium |
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Therapeutic Drug Monitoring,
Volume 15,
Issue 1,
1993,
Page 18-24
L. Gram,
M. Hansen,
S. Sindrup,
K. Brøsen,
J. Poulsen,
T. Aaes-Jørgensen,
K. Overø,
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摘要:
The pharmacokinetic interactions between the selective serotonin reuptake inhibitor citalopram, given as an oral dose of 40 mg/day for 10 days, and (1) levomepromazine (50 mg single oral dose), (2) imipramine (100 mg single oral dose), and (3) lithium (30 mmol/day orally for 5 days) were examined in three panels each of 8 healthy young male volunteers (age 20–31). All volunteers were classified as extensive metabolizers of sparteine and mephenytoin. Each subject completed three study phases—one with citalopram alone, one with one of the three other drugs alone, and one with citalopram combined with the corresponding other drug. For citalopram and its metabolites, a nonenantioselective analytical method (high-performance liquid chromatography) was used. Only two statistically significant interactions were indicated. First, levomepromazine caused a 10–20% increase from the initial steady-state levels of the primary citalopram metabolite, desmethylcitalopram. Second, citalopram caused ∼50% increase in the single-dose area under the serum concentration/time curve of desipramine (primary metabolite or imipramine) and a corresponding reduction in the level of the subsequently formed metabolite 2-hydroxydesipramine. These findings are in agreement with the recent observations that (1) the demethylation of desmethylcitalopram (to didesmethyl-citalopram) is partly mediated via the sparteine/debrisoquine oxygenase (CYP2D6) and that levomepromazine is a potent inhibitor of CYP2D6, and (2) that desmethylcitalopram has a somewhat stronger affinity for CYP2D6 than desipramine, and therefore may inhibit the hydroxylation of desipramine, which is also a substrate of CYP2D6.
ISSN:0163-4356
出版商:OVID
年代:1993
数据来源: OVID
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4. |
A Sensitive High‐Performance Liquid Chromatographic Method for the Determination of 6‐Mercaptopurine in Plasma Using Precolumn Derivatization and Fluorescence Detection |
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Therapeutic Drug Monitoring,
Volume 15,
Issue 1,
1993,
Page 25-30
David Warren,
Lars Slørdal,
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摘要:
A sensitive high-performance liquid chromatographic (HPLC) method for measuring plasma concentrations of 6-mercaptopurine (6-MP) is described. After protein precipitation with 5-sulfosalicylic acid, samples are subjected to precolumn derivatization using the thiol-reactive fluorophore monobromobimane (mBrB). The drug-mBrB adduct is then resolved by isocratic elution from a C18reversed-phase support and quantified by fluorescence detection. Recovery of 6-MP after protein precipitation was consistently >85% and the drug-mBrB adduct was found to be stable for at least 2 weeks at room temperature. With plasma samples containing 30 nM6-MP, the assay displayed within-run (n = 6) and between-day (n = 6) coefficients of variation of 2.2 and 10.6%, respectively. The limit of detection for 6-MP in plasma was 3 nM(500 pg/ml) and the standard curve was linear up to 3 μM. Using this method, we have observed that 6-MP is stable in heparinized whole blood for at least 24 h provided samples are maintained on ice. Since this method requires few manipulations during sample preparation and is readily adaptable to automated techniques, it may prove useful in the routine clinical laboratory setting.
ISSN:0163-4356
出版商:OVID
年代:1993
数据来源: OVID
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5. |
Free Phenytoin Monitoring in Serum and Saliva of Epileptic Patients in China |
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Therapeutic Drug Monitoring,
Volume 15,
Issue 1,
1993,
Page 31-34
Wei Cai,
Guang Zhu,
Gang Chen,
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摘要:
Twenty-three serum samples and 13 saliva samples from 14 Chinese epileptic patients treated with phenytoin (DPH) were obtained to study the correlations between total, free serum, and saliva DPH concentrations. The binding of DPH to serum protein was assessed by equilibrium dialysis, and total and free DPH concentrations were analyzed with a domestic fluorescence polarization immunoassay reagent by the TDx system. A strong correlation existed between the total and free concentrations (r= 0.90, n = 20,p< 0.001). The mean value for the DPH free fraction was 11.13 ± 3.65%. The mean, value for the saliva fraction was 9.40 ± 2.60%. This is the first attempt to monitor free DPH concentrations in serum in Chinese patients.
ISSN:0163-4356
出版商:OVID
年代:1993
数据来源: OVID
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6. |
A Method for Rapid Determination of Lorazepam by High‐Performance Liquid Chromatography |
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Therapeutic Drug Monitoring,
Volume 15,
Issue 1,
1993,
Page 35-38
T. Kondo,
D. Buss,
P. Routledge,
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摘要:
A new sensitive method using solid-phase column extraction and high-performance liquid chromatography (HPLC) has been developed for the determination of lorazepam and its glucuronide metabolite in human plasma. Extraction was performed with a C2-Bond Elut column followed by reverse-phase HPLC of the sample. The detection limit of lorazepam in plasma was 0.5 μg/L. Standard curves over the concentration range from 2.5 to 75 μg/L had good linearity. Intra-assay variability ranged from 2.0 to 6.2% and interassay variability from 4.8 to 8% at the concentration range of 5–50 μg/L.
ISSN:0163-4356
出版商:OVID
年代:1993
数据来源: OVID
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7. |
Influence of Single and Repeated Doses of Oxcarbazepine on the Pharmacokinetic Profile of Felodipine |
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Therapeutic Drug Monitoring,
Volume 15,
Issue 1,
1993,
Page 39-42
G. Zaccara,
P. Gangemi,
L. Bendoni,
G. Menge,
S. Schwabe,
G. Monza,
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摘要:
Eight healthy male volunteers (age 25–41 years) entered an open-label, within-subject study. They were treated for 13 consecutive days with felodipine (FEL) extended-release tablets, 10 mg daily. On day 6, oxcarbazepine (OXC) 600 mg was given in the morning, and from day 7 to 13, the daily dose was increased to 450 mg b.i.d. Blood samples for measurement of FEL and its pyridine metabolite (determined by gas-chromatography) were drawn just before dosing and at 2, 4, 6, 8, 10, 12, and 24 h after dosing on days 5, 6, and 13. Steady-state pharmacokinetic parameters of FEL and its pyridine metabolite were not influenced by the single dose of OXC. Repeated coadministration of OXC significantly reduced the area under the concentration-time curve (AUC0–24) of FEL by 28% and the FEL maximum plasma concentration (Cmax) by 34%. This reduction in FEL bioavailability is much smaller than that observed after co-administration of carbamazepine (CBZ) (i.e., 94%).
ISSN:0163-4356
出版商:OVID
年代:1993
数据来源: OVID
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8. |
Lack of Pharmacokinetic Interaction Between Chloroquine and Imipramine |
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Therapeutic Drug Monitoring,
Volume 15,
Issue 1,
1993,
Page 43-46
Cyprian Onyeji,
Theophilus Toriola,
Festus Ogunbona,
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摘要:
The pharmacokinetic interaction between chloroquine (CQ) and imipramine was investigated in six healthy volunteers who received 300 mg of CQ, 50 mg of imipramine, and combined doses of both drugs in a randomized, crossover design. Blood and urine samples were collected at predetermined time intervals and were analyzed for the drugs and their metabolites by high-performance liquid chromatography methods. The results revealed that the plasma concentrations of CQ and its pharmacokinetic parameters were not significantly altered when CQ was coadministered with imipramine (p> 0.1). The plasma concentration-time profiles and the disposition characteristics of imipramine also were not altered after coadministration with CQ. The results suggest that there appears to be no pharmacokinetic interaction between CQ and imipramine given as single oral doses.
ISSN:0163-4356
出版商:OVID
年代:1993
数据来源: OVID
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9. |
Determination of a Gentamicin Loading Dose in Neonates and Infants |
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Therapeutic Drug Monitoring,
Volume 15,
Issue 1,
1993,
Page 47-51
W. Semchuk,
J. Borgmann,
L. Bowman,
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摘要:
The use of gentamicin as a co-therapy for the treatment of sepsis is common practice in neonates and infants. Gentamicin dosing guidelines have been developed over the past 20 years to accommodate a slower renal elimination rate of gentamicin in the neonatal population. Recently, it has become evident that early attainment of serum gentamicin concentrations ≤5 μg/ml results in a greater therapeutic outcome in septic adult patients. As neonatal immunity is immature and aminoglycosides have an extended elimination half-life in the very young population, reassessment of the initial gentamicin dose has become necessary. Using retrospective data, we determined the amount of gentamicin necessary to effectively “load” a group of neonatal/pediatric patients to achieve initial serum concentrations of 6 or 8 μg/ml. One hundred sixty-six patients less than 12 months postnatal age were studied. The mean initial dose delivered was 2.41 mg/kg. Younger patients demonstrated larger gentamicin apparent volumes of distribution and slower elimination half-lives than did older patients. Initial serum gentamicin concentrations calculated from steady-state pharmacokinetic parameters were significantly lower than those seen at steady state. In order to achieve initial serum gentamicin concentrations > 6 μg/ml an initial dose of 3 mg/kg would be necessary in the group of patients studied. Younger patients (≤34 weeks gestational age) would likely require 4 mg/kg as an initial dose.
ISSN:0163-4356
出版商:OVID
年代:1993
数据来源: OVID
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10. |
Validation of Tobramycin Monitoring in Adolescent and Adult Patients with Cystic Fibrosis |
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Therapeutic Drug Monitoring,
Volume 15,
Issue 1,
1993,
Page 52-59
D. Touw,
A. Vinks,
H. Heijerman,
W. Bakker,
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摘要:
The predictive performance of a dosage calculation method for the optimization of tobramycin therapy was studied retrospectively in 29 patients with cystic fibrosis. The dosage calculation method was based on a linear one-compartment open model. It used peak and trough serum concentrations of the aminoglycoside. Bias in the peak concentration was 0.20 mg/L and precision was 1.2 mg/L. Bias in the trough concentration was −0.06 mg/L and precision was 0.33 mg/L. The results were clinically satisfactory. Comparison with previously published results of the predictive performance of other dosage calculation methods showed that the method studied was at least as good.
ISSN:0163-4356
出版商:OVID
年代:1993
数据来源: OVID
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