摘要:

The present study investigated the potential of therapeutic drug monitoring data to document pharmacokinetic drug interactions with psychotropic medication, both in terms of methodology and applicability. It focused on 105 patients exposed to one of five agents known for their capacity to induce (phenytoine, phenobarbital, and carbamazepine) or to inhibit (thioridazine and levomepromazine) the metabolism of psychotropic drugs. These patients were matched by gender, age, and monitored psychotropic medication to 105 patients randomly selected from a pool of subjects non-exposed to target comedication. Such a paired approach was shown to be effective in reducing variability for a majority of substances. Power analysis suggested that eight to 10 pairs of exposed and nonexposed patients would effectively allow the detection of twofold effects of interacting substances. In keeping with the literature, analysis of the ratios of dose-normalized exposed to nonexposed concentrations indicated that phenothiazine comedication led to significantly higher concentrations of desmethylated metabolites but not parent compounds, when clomipramine, imipramine, or amitriptyline were administered. A similar, as yet undocumented interaction was observed for the tetracyclic antidepressant mianserine. In contrast, the present study revealed that maprotiline concentrations were increased, but its metabolite was largely unaffected by phenothiazine comedication. Increased concentrations were also observed for moclobemide, but not citalopram or its metabolite. In addition to its long recognized capacity to decrease haloperidol concentrations, carbamazepine was shown to induce the metabolism of clopenthixol and possibly flupenthixol. The consistency of such a picture substantiates the need to consider therapeutic drug monitoring databases as cost-effective and reliable tools for postmarketing surveillance.

ISSN:0163-4356    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Our aim was to evaluate the isolated placental lobule to study maternofetal transplacental digoxin transfer and accumulation in placental tissue in vitro. Digoxin passage across the isolated lobule of 10 human placentas was calculated from repeated fetal and maternal perfusate samples, and placental tissue digoxin concentrations were measured at the end of the experiments. To determine the degree of overlap of the fetal and the maternal circulation, the antipyrine clearance was used. Digoxin disappearance from the maternal circuit was not significantly affected by the degree of overlap. In contrast, the increase of digoxin in the fetal compartment was significantly higher in "well-perfused" placentas (antipyrine clearance > 1.60 ml/min; n = 5) than in "malperfused" placentas (antipyrine clearance < 1.50 ml/min; n = 5) (end-feto to initial maternal digoxin ratio 0.44 ± 0.08 vs. 0.30 ± 0.08; p < 0.05), whilst the accumulation in placental tissue was higher in the latter group (0.45 ± 0.07 vs. 0.62 ± 0.10 ng/mg protein; p < 0.05). We conclude that the isolated placental lobule is suitable to quantify transplacental digoxin transfer in vitro, but the diffusion characteristics of each preparation have to be considered.

ISSN:0163-4356    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Cyclosporin A (CyA) is the primary immunosuppressive agent for the prophylaxis of rejection episodes in renal, cardiac, liver, and other transplants. Recently, its use in autoimmune diseases has been investigated as well. Although several studies have produced promising results, nephrotoxicity and hypertension can result from CyA treatment, and their development must be understood in order to facilitate patient management. This article describes the diastolic blood pressure (DBP) responses in two populations of patients during three months of CyA therapy. Study A involved psoriasis patients and Study B involved postoperative renal transplant patients. The relationship between blood pressure and systemic CyA exposure and other covariates was evaluated using linear mixed effects modeling. Temporal patterns of blood pressure changes with varying duration of CyA exposure were investigated. In Study A, the psoriasis patients showed transient exposure-related increases in DBP on CyA. These elevations, while statistically significant, were clinically insignificant. In Study B, the renal transplant patients showed no CyA-related rises in DBP. In neither study was there evidence for a difference in effect on DBP between Sandimmune and Neoral, the two formulations of CyA presently approved for marketing by the Food and Drug Administration, after differences in CyA exposure were taken into account.

ISSN:0163-4356    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Neural network (NN) computation is computer modeling based in part on simulation of the structure and function of the brain. These modeling techniques have been found useful as pattern recognition tools. In the present study, data including age, sex, height, weight, serum creatinine concentration, dose, dosing interval, and time of measurement were collected from 240 patients with various diseases being treated with gentamicin in a general hospital setting. The patient records were randomly divided into two sets: a training set of 220 patients used to develop relationships between input and output variables (peak and trough plasma concentrations) and a testing set (blinded from the NN) of 20 to test the NN. The network model was the back-propagation, feed-forward model. Various networks were tested, and the most accurate networks for peak and trough (calculated as mean percent error, root mean squared error of the testing group, andrvalue between observed and predicted values) were reported. The results indicate that NNs can predict gentamicin serum concentrations accurately from various input data over a range of patient ages and renal function and may offer advantages over traditional dose prediction methods for gentamicin.

ISSN:0163-4356    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Information about the pharmacokinetics of felbamate in children is limited. Even though it is claimed that monitoring of felbamate concentrations is unnecessary, many neurologists have requested therapeutic drug monitoring (TDM) for various reasons. This study used the NONMEM program to describe the pharmacokinetics and the influence of other anticonvulsants on the pharmacokinetics of felbamate. Felbamate, carbamazepine (CBZ), phenytoin (PHY), valproate (VPA), and barbiturate serum levels were obtained by our TDM service as requested by the clinician. The clearance and volume of distribution of felbamate were 41.1 ml/h/kg and 908 ml/kg, respectively. CBZ and PHY increased the clearance 49 and 40% while VPA decreased it 21%. Barbiturate had no significant effect. Clearance also decreased with age.

ISSN:0163-4356    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Two identical open-label, randomized crossover studies were conducted to compare serum estradiol profiles from the new 12.5- and 25-cm2once-a-week adhesive patches with those from the 10- and 20-cm2commercially available twice-a-week Estraderm patches when applied as directed during a 1-week patch-wear period. Both studies were conducted in healthy postmenopausal women; serum estradiol levels were determined by gas chromatography/mass spectroscopy (GC/MS). Although both sizes of both patch treatments produced mean serum estradiol levels in the therapeutic range, the once-a-week patch provided more constant mean levels, avoiding large peak-to-trough fluctuations. As expected, the differences in mean serum estradiol concentrations between the two patch treatments occurred during the second application of the twice-a-week patch. Based on these results, the once-a-week drug in adhesive patch appears to be an acceptable means of hormone replacement therapy.

ISSN:0163-4356    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Our previous study suggested that cytochrome P4502D6 (CYP2D6) is involved in the metabolism of trazodone and its active metabolite, m-chlorophenylpiperazine (m-CPP). The purpose of this study was to examine the degrees of increase in plasma concentrations of trazodone and m-CPP induced by haloperidol, which is an inhibitor of CYP2D6. The subjects were nine depressed inpatients receiving trazodone at bedtime (150 mg in seven patients and 300 mg in two) for 2-19 weeks. Haloperidol at 4 mg/day was coadministered for 1 week, and blood samplings were taken before and after the coadministration. Contrary to our expectation, haloperidol did not significantly increase the mean plasma trazodone concentration (810 ± 382 vs. 856 ± 357 ng/ml). However, haloperidol significantly increased (p< 0.01) the mean plasma m-CPP concentration (78 ± 31 vs. 92 ± 34 ng/ml).

ISSN:0163-4356    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

We conducted a randomized study with four parallel groups to investigate the effect of single and multiple doses of activated charcoal on the absorption and elimination of pholcodine administered in a cough syrup. The first group received 100 mg of pholcodine on an empty stomach with water only (control); the second group took 25 g of activated charcoal immediately after pholcodine; the third group received 25 g of activated charcoal 2 h and the fourth group 5 h after ingestion of the 100-mg dose of pholcodine. In addition, the fourth group received multiple doses (10 g each) of charcoal every 12 h for 84 h. Blood samples were collected for 96 h and urine for 72 h. Pholcodine concentrations were measured by high-performance liquid chromatography. A significant reduction in absorption was found when charcoal was administered immediately after pholcodine; the AUC0-96hwas reduced by 91% (p < 0.0005), the Cmaxby 77% (p < 0.0005), and the amount of pholcodine excreted into urine by 85% (p < 0.0005). When charcoal was administered 2 h after pholcodine, the AUC0-96hwas reduced by 26% (p = 0.002), the Cmaxby 23% (p = NS), and the urinary excretion by 28% (p = 0.004). When administered 5 h after pholcodine, charcoal produced only a 17% reduction in the AUC0-96h(p = 0.06), but reduced the further absorption of pholcodine still present in the gastrointestinal tract at the time of charcoal administration, as measured by AUC5-96h(p = 0.006). Repeated administration of charcoal failed to accelerate the elimination of pholcodine. We conclude that activated charcoal is effective in preventing the absorption of pholcodine, and its administration can be beneficial even several hours after pholcodine ingestion.

ISSN:0163-4356    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Albendazole is considered the drug of choice for neurocysticercosis. It is frequently used in combination with dexamethasone to prevent the acute inflammatory reaction due to cysticercal death. It has been reported that dexamethasone increases the plasma level of albendazole sulfoxide, the active metabolite of albendazole. The pharmacokinetic interaction of albendazole sulfoxide with dexamethasone, associated or not with cimetidine, was investigated in 24 patients with active intraparenchymal brain cysticercosis. Eight of these patients received albendazole alone, eight received it in combination with dexamethasone, and eight received it in combination with both dexamethasone and cimetidine. The pharmacokinetic parameters maximum plasma concentration, time to maximum plasma concentration, absorption half-life, and absorption rate constant did not differ between groups, suggesting that the formation of albendazole sulfoxide was not altered by the administration of dexamethasone, combined or not with cimetidine. There were significant differences, however, in the parameters plasma concentration-time curve, oral clearance, elimination half-life, and elimination rate constant, suggesting that dexamethasone, combined or not with cimetidine, decreases the rate of elimination of albendazole sulfoxide.

ISSN:0163-4356    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Theophylline is predominantly metabolized by cytochrome P4501A2 (CYP1A2). A possible interaction between griseofulvin and theophylline was reported to our laboratory, which led us to form the hypothesis that griseofulvin induces the metabolism of theophylline. One purpose of this study was to investigate this hypothesis. The study was carried out as a randomized crossover study of 12 healthy volunteers. In period A of the study, each volunteer received a single dose of 300 mg theophylline ethylenediamine orally. In period B, the subjects took fluvoxamine, 50 mg for 1 day and 100 mg for 6 days, and on day 4, the subjects ingested 300 mg theophylline ethylenediamine. Fluvoxamine is a potent inhibitor of CYP1A2, and period B was included as a positive control. In period C, the subjects took 500 mg griseofulvin for 9 days; on day 8 the subjects again ingested 300 mg theophylline ethylenediamine. Theophylline and its metabolites (1-methyluric acid [1MU], 3-methylxanthine [3MX], and 1,3-dimethyluric acid [13DMU]) in plasma and urine were assayed by high-performance liquid chromatography. During fluvoxamine intake, the median of the total clearance of theophylline decreased from 80 ml/min to 24 ml/min, and the half-life increased from 6.6 to 22 h. The partial formation clearances of the metabolites decreased from 17 to 1.7 ml/min, from 8.9 to 0.9 ml/min, and from 21 to 6.8 ml/min for 1MU, 3MX, and 13DMU, respectively. The results confirm that assessment of theophylline metabolism indeed serves as a biomarker for CYP1A2. During griseofulvin ingestion, the median of the total and partial clearances of theophylline were 84 ml/min, 22 ml/min (1MU), 9.4 ml/min (3MX), and 25 ml/min (13DMU). The half-life decreased significantly from 6.6 to 5.7 h. The increase in partial formation clearances of 1MU and 13DMU, but not of 3MX, were statistically significant. The increase in the total clearance reached only borderline significance. In four subjects a marked induction was seen for all pharmacokinetic parameters, suggesting that the susceptibility to induction is more pronounced in some subjects. This susceptibility could theoretically be explained by a polymorphism in the inducibility of the gene coding for the CYP1A2 enzyme.

ISSN:0163-4356    

出版商:OVID    

年代:1997

数据来源: OVID