摘要:

SummaryTherapeutic drug monitoring data for amitriptyline (AT) and nortriptyline (NT) collected during 10 years (total of 4,278 analyses in 2,937 patients) were evaluated to study how other drugs affect the kinetics at steady state. The distribution of the ratio concentration/daily dose (C/D) in patients treated with the antidepressant only was compared with that in patients on different concomitant drugs. Patients on phenothiazines or dextro-propoxyphene had a significantly higher mean CID of NT than controls, both when AT and when NT had been given. The highest values were seen with levomepromazine and thioridazine. On the contrary, the mean CID of both AT and NT in patients on carbamazepine was about 50% lower than in those treated with the antidepressant only. Benzodiazepines did not affect the steady-state kinetics of AT or NT. Intraindividual comparisons of the ratio CID in subjects with analyses performed when off and on concomitant drugs corroborate previous results showing that drugs metabolized by the debrisoquine hydroxylase (CYP2D6) inhibit the metabolism of NT and that carbamazepine induces the metabolism of both AT and NT. Modeling of the dose dependency of the NT interactions with levomepromazine, perphenazine, and thioridazine revealed that the ratio CID was most affected at low doses of the antidepressant and at high doses of the phenothiazine. The distribution of the doses given was the same in patients on monotherapy as in patients with interacting drugs, which means that many patients treated with phenothiazines had concentrations above the therapeutic range and that most patients treated with carbamazepine had subtherapeutic levels. The present study shows that therapeutic drug monitoring may serve as a valuable tool to discover and quantify drug interactions.

ISSN:0163-4356    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryThe purpose of this study was to examine the pharmacokinetics of mercaptopurine (6-MP) and thioguanine nucleotides (6-TGN) during azathioprine treatment. Plasma profiles and urinary excretion of 6-MP and 6-TGN concentrations in red blood cells (RBCs) were measured repeatedly during the first 3 weeks following transplantation in 10 adults, who had received kidney grafts from living related donors. Mean maximal 6-MP plasma concentration (Cmax) was 340 nmol/L (SD = 290), mean time to Cmax(7max) was 2 h (SD = 1.8), and mean area under the plasma concentration-time curve (AUC) was 930 nmol/L/h (SD = 770). The mean fraction of azathioprine dose excreted as 6-MP in urine was 1.32% (SD = 1.11). Up to eightfold variability of Cmaxand AUC was observed from day to day within each patient. The correlation between 6-MP AUC and amount excreted in the urine was weak (r = 0.37, 95% CI from 0.02 to 0.64). In this group of patients the observed 6-TGN levels in RBCs were low; maxima during the observation period ranged from undetectable to 250 pmol/8 x 108RBCs. In individual patients, 6-TGN levels were relatively stable throughout the dosing interval (“within-dose-interval-CV” < 19%), even when sharp and high 6-MP peaks in plasma were observed.

ISSN:0163-4356    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryImmunization of New Zealand white rabbits with a bovine serum albumin conjugate of 7-hydroxy-N-carboxyethyl-N-deshydroxyethylfluphenazine produced highly specific antisera for 7-hydroxyfluphenazine (7-OHFLU). A radioimmunoassay (RIA) was developed using antisera from one of the rabbits that enabled for the first time the determination of plasma levels of 7-OHFLU, an active metabolite of fluphenazine (FLU), in patients treated with oral FLU dihydrochloride or i.m. FLU decanoate. The assay method provided sufficient sensitivity to determine accurately 20 pg of 7-OHFLU in 200 μl (0.1 ng/ml) of plasma with a coefficient of variation of <10%. The antiserum used in the RIA for 7-OHFLU demonstrated negligible cross-reactivity with FLU and its metabolites such as FLU sulfoxide, N-deshydroxyethylFLU, FLU N4'-oxide, N-deshydroxyethyl-7-OHFLU, and 7-O-glucuronide of FLU and also with other antipsychotic agents and commonly coadministered drugs. The 7-OHFLU was present in measurable amounts in all plasma samples obtained at 4-week intervals from patients receiving a daily oral dose of 5 (n = 10), 10 (n = 13), or 20 (n = 14) mg of FLU dihydrochloride. Large interindividual variations in the plasma level of FLU and 7-OHFLU were noted and the mean plasma levels ratios of 7-OHFLU/ FLU at these doses were 2.07 ± 1.08, 2.07 ± 1.13, and 2.02 ± 0.82, respectively. In the case of plasma samples from patients treated with a biweekly i.m. dose of 5 mg of FLU decanoate, 7-OHFLU could be determined in 64% of the plasma samples where the mean plasma level ratio of 7-OHFLU/FLU was 0.60 ± 0.45. These data indicate that 7-OHFLU is a major metabolite when FLU is administered either orally or intramuscularly to schizophrenic patients.

ISSN:0163-4356    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryPlasma concentrations of chlorpromazine (CPZ) and six metabolites were measured in 12 chronic schizophrenic patients on a fixed dose of CPZ. All six metabolites were measured in significant concentrations, ranging from 12 to 57% of the parent drug concentration. They are listed in order of decreasing mean concentration as follows: chlorpromazine-N-oxide > chlorpromazine sulfoxide > 7-OH chlorpromazine > Nor2chlorpromazine sulfoxide > Nor2chlorpromazine > Nor1chlorpromazine. CPZ concentrations showed significant correlation with the 7-OH chlorpromazine metabolite concentration. Since these metabolites have been associated with in vitro activity and occur in significant concentrations, it is recommended that all six metabolites be measured in studies correlating drug levels with pharmacodynamic effects.

ISSN:0163-4356    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryThe application of three non-steady-state sampling strategies and the fitting of either three or five pharmacokinetic parameter estimates by a two-compartment Bayesian forecasting program was evaluated retrospectively in 27 adult patients with stable renal function. Sampling strategies included a single midpoint concentration, a set of peak and trough concentrations, and three serial vancomycin concentrations. The most precise and least-bias predictions of steady-state peak vancomycin concentrations were observed by using population-based parameter estimates [mean prediction error (ME) = −0.40 and mean absolute error = 5.77]. The addition of non-steady-state feedback concentration(s) did not provide additional information for predictions of future steady-state peak concentrations. The least-bias prediction of steady-state trough vancomycin concentrations was seen when a single midpoint non-steady-state concentration was used (ME = 0.92 and −0.17 for five and three fitted parameter estimates, respectively). The MEs of serial and peak and trough feedback strategies were similar in magnitude to those obtained using population parameters, but in opposite directions (underprediction vs. overprediction, respectively). The fitting of only three parameters produced results similar to those using five parameters. The results from this study confirm our previous evaluation that non-steady-state concentrations provide very minimal information to Bayesian forecasting of future steady-state concentrations.

ISSN:0163-4356    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryWe report five cases where fluvoxamine (FLVX) was added to maintenance treatment with methadone (MTD) in addict patients with affective disorders. In view of the implication of FLVX in several metabolic drug interactions, MTD plasma levels were measured before and after treatment with FLVX. A slight increase (∼20% of the MTD plasma level/dose ratio) occurred in two cases. In the remaining three patients, the interaction was more pronounced (40–100% increase of the MTD plasma level/dose ratio), with clinical manifestations of opiate withdrawal after stopping FLVX therapy in one case. Caution is needed when starting or stopping treatment with FLVX in patients receiving maintenance treatment with methadone.

ISSN:0163-4356    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryRecently it has been recognized that steady-state serum digoxin concentrations may increase or fall to ineffective levels when the glycoside is administered together with several antibiotics. Our study was designed to assess if serum digoxin levels may be modified by the concomitant use of a ticarcillin and clavulanic acid. The study was carried out in 15 hospitalized patients suffering from exacerbation of their chronic bronchitis without liver disease and renal failure. Serum digoxin levels were not significantly modified by the concomitant use of a ticarcillin and clavulanic acid, although peak digoxin serum concentrations were slightly lower. However, the average time to achieve the maximum concentration and area under the curve over 24 h did not change.

ISSN:0163-4356    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryOn the basis of reports that diltiazem may bind to the hepatic mi-crosomal enzymes and inhibits the metabolism of some co-administered drugs, and to determine the effects of diltiazem on theophylline pharmacokinetics in patients with bronchospastic airway disease, we have investigated the effect of a 180-mg daily dose of oral diltiazem during 5 days on theophylline clearance in eight patients with that disease. Theophylline half-life increased 24%, from 5.7 ± 1 to 7.5 ± 1.8 h (p < 0.05), and total body theophylline clearance showed a decrease of 22%, from 87.3 ± 20 to 68.3 ± 18.6 ml/min (p < 0.05) after diltiazem therapy. The apparent volume of distribution was unchanged. This reduction in theophylline clearance is likely produced by inhibition of its metabolism by diltiazem. A clinically important drug interaction may occur with theophylline when diltiazem therapy is given concurrently in patients with bronchospastic airway disease.

ISSN:0163-4356    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryPhenytoin is frequently used to treat seizure episodes in critically ill patients. Some of these patients have acute renal failure, requiring continuous hemofiltration to help maintain fluid and solute balance. We evaluated the removal of phenytoin in patients who received the drug while undergoing continuous hemofiltration treatment. Arterial and ultrafiltrate sample pairs were collected for phenytoin concentration determination. The ultrafiltrate drug concentrations were almost identical to the free serum phenytoin concentrations. Thus the ultrafiltrate/arterial drug concentration ratios resembled the percentages of serum free drug. Between 0.32 and 0.78 mg of phenytoin/h was removed by hemofiltration. The magnitude of hemofiltration phenytoin removal was related to the free drug concentration, total serum drug concentration, and ultrafiltration flow rate. When the ultrafiltration flow rate was low, the amount of phenytoin removed by hemofiltration was small relative to the usual daily dose. However, in patients with renal failure in whom serum phenytoin protein binding is substantially reduced, continuous hemofiltration at a high ultrafiltration rate may remove a clinically significant amount of the drug. Higher daily doses of phenytoin may be needed to maintain the therapeutic effect. Serum drug concentration monitoring will be necessary to determine the optimal dosage regimen.

ISSN:0163-4356    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

SummaryTo assess the reliability of salivary theophylline concentrations for patient monitoring, concentrations of theophylline in sera and saliva of 50 patients (ages 6–81 years) receiving oral or parenteral theophylline were determined by two methods: a rapid dry-phase apoenzyme reactivation system (ARIS) and fluorescence polarization immunoassay (FPIA). Saliva production was stimulated by both citric acid (CA) and parafilm (PF). With both analytical methods, there were excellent correlations between salivary theophylline concentration, Cs, and unbound serum theophylline concentration Cu(r2> 0.95), and between Csand total serum theophylline concentration, CT(r2> 0.85). CA- and PF-stimulated Csby FPIA resulted in concentrations within 2.0 μg/ml of the actual Cufor 100% of the samples measured (n = 47). By ARIS, 100% of the PF-stimulated Csand 93.6% of the CA-stimulated Csdeterminations were within 2.0 μg/ml of the Cu(n = 47). To evaluate the predictive capabilities of PF- and CA-stimulated saliva, one-half (n = 24) of the patients were randomly selected and their data used to predict the CTfor the remaining patients. FPIA PF-CSpredicted 83.3% (20/24) of CTwithin ±2 μg/ml, while ARIS CA-CSpredicted 75.0% within ±2 μg/ml. There was no difference between FPIA Csand ARIS Csresults by multivariate analysis of variance (MANOVA), but there was a difference between PF-CSand CA-Cs(p < 0.05). However, when Cuwas used as a covariant, there was no significant difference. Using appropriate saliva collection procedures and the FPIA system, we conclude that Csprovides adequate reliability for therapeutic drug monitoring of theophylline.

ISSN:0163-4356    

出版商:OVID    

年代:1994

数据来源: OVID