摘要:

Plasma levels of 6-mercaptopurine were determined in 22 consecutive children with acute lymphoblastic leukemia on oral remission maintenance therapy during the time period of August 1984 to January 1988. Each child received the drug once daily for up to 3 years and was studied repeatedly (1–12 times). An HPLC method was used for drug analysis. We found large interpatient variations in the mean peak plasma concentration (range of 50–424 ng/ml) and in the mean area under the concentration vs. time from 0–4 h curve (range of 82–637 ng ml-1h). There were also pronounced variations between different sampling occasions in the same patient. Nine of the 22 patients had complications during the maintenance therapy. Five children with a mean peak plasma level below 135 ng/ml and a mean area under the curve (AUC) value below 251 ng ml-1h relapsed (three in the central nervous system and two in the bone marrow). Both children with a bone marrow relapse died. Relapse risk was related to the AUC (p< 0.05). Four children with a mean peak plasma level above 166 ng/ml and a mean AUC value above 363 ng/ml/h developed severe myelotoxicity, which necessitated a temporary cessation of the maintenance therapy. In addition, two patients relapsed 6 and 11 months after termination of maintenance therapy. Their mean peak and AUC values were not low but the concentrations decreased markedly towards the end of the maintenance period. The results indicate that the plasma levels of 6-mercaptopurine, when determined repeatedly, might be of significance for the outcome of the remission maintenance treatment.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The protein binding of cyclosporine (CyA) in plasma was studied in serial samples for 6 months after transplantation in 66 renal transplant recipients. Analysis was performed with a recently developed method of equilibrium dialysis in steel chambers. Among the 1,848 samples, the free fraction ranged from 0.5 to 4.2%, with a median of 1.30%. The free fraction of CyA was highest immediately after transplantation (1.66 \Pm 0.49%). Diabetics had a higher free fraction of CyA than nondiabetics during the first 2 weeks after transplantation. A weak, but significant, covariation was observed between the serum concentration of albumin or bilirubin and the free fraction of CyA (r= −0.47 andr= 0.39, respectively;p< 0.01). There was also a significant correlation between serum HDL cholesterol (r= −0.39 to −0.48;p< 0.01), as well as apolipoprotein Al (r= −0.35 to −0.49;p< 0.01), and the free fraction of CyA. A significant drop in the free fraction of CyA was observed immediately prior to acute rejection episodes as compared with I week earlier (p< 0.01), but there was no difference in the free fraction of CyA between patients who lost their graft and those who did not. There was an overall eightfold variation in the free fraction of CyA in plasma, with an up to fivefold intraindividual variation and a 2.3-fold variation in the mean free fraction between individuals. A significant covariation was observed between the free fraction of CyA and the concentration of binding proteins in plasma, as well as factors such as time after transplantation, diagnosis, and clinical events. Thus, it is now possible to monitor free CyA, and this may prove useful in special situations, for example, in patients with dyslipoproteinemias.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The alterations in aminoglycoside disposition in patients previously treated with cisplatin were determined by reviewing the medical records of 37 cancer patients. The patients received 44 courses of an aminoglycoside antibiotic (gentamicin, n = 27; amikacin, n = 14; and tobramycin, n = 3). The mean (SD) half-life of 171 (120) min was greater than our previously published mean aminoglycoside half-life in children with cancer who were not receiving cisplatin. Twenty-five of 44 courses were completed without an aminoglycoside dosage reduction and only 5 courses were discontinued because of delayed aminoglycoside elimination. There was no significant difference in the duration of aminoglycoside therapy between the group that had a dosage reduction and the group that did not [6.6 (2.3) versus 5.8 (2.9) days,p= 0.42, respectively]. Multiple linear regression analysis of patient variables identified serum creatinine and cumulative cisplatin dose as the best predictors of aminoglycoside half-life (r2= 46.0%,p< 0.001). The only predictor of aminoglycoside clearance was serum creatinine (r2= 35.2%,p< 0.001). Patients previously treated with cisplatin are at greater risk for delayed aminoglycoside elimination. Prior administration of cisplatin is not an absolute contraindication to the use of aminoglycoside antibiotics. When clinically indicated, patients who have previously received cisplatin and have apparently normal renal function should be treated cautiously with standard doses of aminoglycoside antibiotics, and pharmacokinetic monitoring should be routinely performed.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The aim of the present study was to characterize the kinetic behavior of imipramine (IMI) and desipramine in enuretic children and to evaluate the performance of different methods for dosage prediction based on individual and/or population data. The study was carried out in 135 enuretic children (93 boys) ranging in age between 5 and 13 years undergoing treatment with IMI in variable single doses (25–75 mg/day) administered at night. Sampling time was one-half the dosage interval at steady state. The number of data available for each patient varied (1–4) and was essentially limited by clinical criteria. Pharmacokinetic calculations were performed using a simple proportional relationship (method 1) and a multiple nonlinear regression program (MULTI 2 BAYES) with two different options: using the ordinary least-squares method (method 2) and the least-squares method based on the Bayesian algorithm (method 3). The results obtained point to a coefficient of variation for the level/dose ratio of the drug (58%) that is significantly lower than that of the metabolite (101.4%). The forecasting capacity of method 1 is deficient both regarding accuracy [mean prediction error (MPE) = −5.48 \Pm 69.15] and precision (root mean squared error = 46.42 \Pm 51.39). The standard deviation of the MPE (69) makes the method unacceptable from the clinical point of view. The more information that is available concerning the serum levels, the greater are the accuracy and precision of methods (2 and 3). With the Bayesian method, less information on drug serum levels is needed to achieve clinically acceptable predictions.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

During a 3-month period, 52 paranoid psychotic inpatients were treated with perphenazine decanoate (Trilafon decanoate) in order to determine a treatment schedule ensuring perphenazine serum levels within the optimal range (2–6 nmol/L). All patients received 1 ml (108 mg) perphenazine decanoate on days 0, 7 and 21, after which the doses and intervals were individually adjusted according to the clinical condition. It was shown that the sum of 2 measurements of perphenazine concentration early during treatment, viz., on days 14 and 21, correlates strongly (r= 0.96) with the steady-state level obtained after 3 months. Consequently, a nomogram for dose and length of interval could be elaborated giving steady-state serum levels of perphenazine of about 4 nmol/L, i.e., in the middle of the optimal concentration range.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

To evaluate the ability of clinicians to accurately dose antiepileptic drugs (AEDs), 2,958 serum concentrations in two outpatient epilepsy clinics were studied. Serum concentrations of phenytoin (PHT) were significantly less likely to fall within the therapeutic range (TR) when compared to carbamazepine (CBZ) or phenobarbital (p< 0.0001) even when there was evidence that patient compliance was good. This difference remained significant when the second through fourth follow-up serum concentrations were analyzed. PHT concentrations were more likely to be below than above the TR (p< 0.0001). CBZ concentrations were least likely of the three AEDs to be below the TR (p< 0.01). Analysis of factors influencing AED metabolism and of data from previous studies implies that saturable metabolism and variable time to steady state for PHT are responsible for these findings. These results support the increased use of dosing aids for PHT that may help clinicians more accurately choose PHT doses and estimate time to steady state.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

Healthy male volunteers (n = 48) aged 18–44 years received a single 10-mg oral dose of diazepam. Plasma diazepam and desmethyldiazepam concentrations were measured at multiple points during the next 11 days. The distribution of peak plasma concentration (mean, 406 ng/ml) was not skewed and did not differ significantly from normal (Gaussian). However, the distributions of elimination half-life (44.2 h), elimination rate constant (0.0219/h), clearance (26.6 ml/min), and volume of distribution (83 L) all were significantly skewed and deviated significantly from normal. After logarithmic transformation, the distributions of elimination rate constant, elimination half-life, and volume of distribution were consistent with normal; however, this was not the case for time of peak plasma concentration. Thus, the pharmacokinetic characteristics of oral diazepam are highly variable even in a relatively homogeneous population. Parametric statistical testing procedures and pharmacokinetic forecasting schemes may be improved by more precise delineation of the underlying distributions for pharmacokinetic variables.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The single-dose prediction model (SDPM) of Slattery et al. has been shown accurately to predict short-term (3 to 7 days) steady-state valproic acid (VPA) concentrations in normal volunteers and in hospitalized patients receiving monotherapy. To assess the long-term usefulness of the SDPM in a real-life clinic setting, six ambulatory patients ranging in age from 2 to 8 years were studied. Blood samples were drawn at least 6 h after the initial dose but before the second dose of VPA. A steady-state trough concentration (Cmin) was measured 3 to 7 days after the initiation of therapy. Dosage adjustments and alterations in therapeutic regimen were allowed and anotherCminwas measured after 1 to 12 months. PredictedCmin, values were calculated for both the short-term and long-term VPA regimens. Predictive performance analysis demonstrated that the SDPM was unbiased in predicting both short-term and long-term VPACmin, values and precise in predicting only short-term VPACminn, values. The SDPM is not a reliable predictor of long-term total VPA concentrations in seizure patients in an outpatient clinic setting.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The relationship between the serum concentration of phenobarbital and its pharmacodynamic effects was assessed in a double-blind controlled study in eight normal volunteers who were given single oral doses of phenobarbital (200 mg) and placebo according to a randomized cross-over design. Compared with the placebo session, phenobarbital was found to induce CNS-depressing effects as assessed by visual analogue rating scales (VARS) and critical flicker fusion tests (CFF), whereas no significant effects were detected on choice reaction times, tappings, and digit symbol substitutions. There was a clear-cut dissociation between the time course of serum phenobarbital levels, which remained at a plateau throughout most of the period of observation (up to 72 h) and its subjective (VARS) and objective (CFF) effects, which could be documented only for up to 9 h after administration. These data suggest that pharmacodynamic tolerance develops rapidly even after a single oral dose of the drug. Multiple Sleep Latency Tests (MSLTs) were also performed in the same subjects and showed that phenobarbital increases diurnal drowsiness and attenuates the circadian variation in drowsy state that is seen under control conditions. MSLTs appeared to be superior to other tests in documenting the sedative effects of the barbiturate.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

The influence of terodiline (25 mg b.i.d.) on the anticoagulant effect and plasma levels of warfarin enantiomers was studied in 23 young healthy male volunteers. Racemic warfarin was first given for 24 days to determine the doses required for the subject's vitamin K-dependent coagulation factors to fall within 10–20% of the normal range, as determined by the Thrombotest. During continuous warfarin treatment (mean daily dose 5.3 mg, range 2.5–9.4 mg), terodiline or placebo was given for two weeks in a randomized and double-blind fashion, and then the drugs were crossed over and given for another two weeks. Terodiline did not influence the anticoagulant effect of warfarin or the plasma levels of the warfarin enantiomers. The results indicate that it should not be necessary to monitor patients on combined therapy with terodiline and warfarin more frequently than patients on warfarin monotherapy.

ISSN:0163-4356    

出版商:OVID    

年代:1989

数据来源: OVID