ISSN:0163-4356    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Protease Inhibitor TDMThis study examines the importance of therapeutic drug monitoring (TDM) of protease inhibitors (PI) in adults and children infected with the human immunodeficiency virus (HIV). Pediatric patients were included because information in this population is limited. A high performance liquid chromatographic (HPLC) assay measured indinavir, saquinavir, ritonavir and nelfinavir simultaneously in 0.2 mL of plasma. Initially, the reliability, sensitivity and specificity of the assay were verified in stored samples of plasma from adult patients who had been receiving PIs. Non-detectable concentrations (ND) were <25–50 ng/mL. In 96 out of 293 stored samples from adult patients, selected randomly, concentrations of PIs were ND. In a second prospective study of 10 adults (9 mothers and one father, aged 24–42 years) and 15 children (2.9–18 years) ND levels of PI were observed frequently (27% or 4 out of 15 pediatric subjects). In the latter study, drug-drug interactions, dosing errors, noncompliance and other important problems were identified and corrected. Routine monitoring and interpretation of PI concentrations (TDM) may improve the management of adult and pediatric patients infected with HIV, especially in those who fail to respond, develop adverse effects or viral resistance, or lack compliance.

ISSN:0163-4356    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The intra- and interindividual variability in apparent steady-state plasma levels of risperidone (RSP) and its metabolite 9-hydroxyrisperidone (9-OHRSP) in schizophrenic patients was investigated. Patients (n = 46, age 26.4 ± 5.3 years) with diagnosed schizophrenia were treated with a fixed daily oral dose of RSP (1–12 mg/d). The steady-state plasma samples from these patients were collected over a period of 5 years and a total of 549 visits. Plasma concentrations of RSP and 9-OHRSP were determined using a highly sensitive and specific LC-MS-MS method with a detection limit of 0.1 ng/mL. All plasma samples had measurable amounts of 9-OHRSP; however, RSP was nondetectable (<0.1 ng/mL) in 18% of the plasma samples. 9-OHRSP levels were, on average, ∼22 times higher than those of RSP. The plasma levels of RSP and 9-OHRSP varied widely among patients receiving similar doses of RSP, and the intra- and interindividual variations of RSP and 9-OHRSP plasma levels were found to be large. The data indicated that there was no significant change in the steady-state levels of either RSP or 9-OHRSP during the treatment period. Similarly, the dose-normalized concentration did not vary significantly during the treatment period or with the administered dose. The absence of RSP in many plasma samples (<0.1 ng/mL) and presence of 9-OHRSP at severalfold higher concentrations than RSP indicate that measuring plasma levels of RSP alone may lead to erroneous interpretation in plasma level monitoring studies. The current data support the fact that it is important to measure steady-state levels of total active moiety by analyzing both RSP and 9-OHRSP for plasma drug monitoring.

ISSN:0163-4356    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Jejunoileal bypass (JIB) is a weight loss procedure in which malabsorption is produced by connecting a short length of proximal jejunum to the distal ileum. Because 90% of the small intestine is bypassed, it may have impact on the dose–concentration response of oral cyclosporine (CsA). The authors characterized the dose-adjusted blood concentrations of CsA obtained 2 hours (C2) after oral microemulsion CsA (ME-CsA) in a liver transplant (LTx) subject with an intact JIB, as compared with those from seven LTx controls without JIB. The biliary reconstruction involved choledochocholedochostomy without external drainage in all patients. ME-CsA was administered via a nasogastric tube within 24 hours after graft reperfusion. Oral fluconazole was given prophylactically to the study subject only for 6 days after LTx. During the first week after LTx, the dose-adjusted C2 (mean ± SD) for the study subject and for controls was 53 ± 10 and 106 ± 47 ng/mL, respectively (P< 0.001). The corresponding value during the period from day 7 to day 107 was 105 ± 40 and 257 ± 86 ng/mL, respectively (P< 0.001). Multiple linear regression revealed that dosage, days after LTx, and the presence of a JIB were all independent predictors of C2 (R2= 0.798,P= 0.037). Lack of bile resulting in malabsorption of ME-CsA was not thought to be significant contributor to her low dose-adjusted C2 because there was no external bile drainage and a portion of terminal ileum, where most bile acid reabsorption occurred, was still available after JIB. The fact that fluconazole failed to increase the dose-adjusted C2 in the study subject supports that enteric clearance of CsA may become clinically unimportant after JIB. Therefore, the low dose-adjusted C2 is most likely explained by the reduced bowel length and associated absorptive surface area after JIB. In conclusion, patients with JIB may require higher doses of ME-CsA.

ISSN:0163-4356    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:0163-4356    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Olanzapine is an atypical antipsychotic effective in the treatment of schizophrenia. The present study has examined the potential use of target concentration monitoring of olanzapine in plasma as a marker of clinical response and an aid in patient management. Fifty-three patients (mean age 32 years; 40 M, 13 F) with a DSM-IVR diagnosis of schizophrenia completed a 6-week trial of oral olanzapine. Participants received once-daily olanzapine, and their psychotic symptoms were measured with the PANSS (Positive and Negative Symptom Scale) on admission and again after 6 weeks. Responders were classified as having a ≥20% decrease in PANSS scores. Plasma olanzapine was quantified by high-performance liquid chromatography. Receiver operator characteristic (ROC) curve analysis was used to identify a break point in plasma olanzapine that might serve as a surrogate for PANSS classification, and the two methods were compared using the McNemar &khgr;2test. After 6 weeks the median olanzapine dose was 15 mg/d (range 5–30 mg/d), and the mean plasma olanzapine was 32 &mgr;g/L at a mean of 13.5 hours after dose. With the PANSS (total), there were 42 responders and 11 nonresponders. ROC curve analysis for total PANSS identified a break point at 23 &mgr;g/L plasma olanzapine, with the proportions of responders and nonresponders identified by PANSS and the plasma break point being similar. Similar break points were found for the positive, negative, and global PANSS subscores. Nevertheless, these relationships were very modest, and at best the target plasma olanzapine concentration identified only 20% more responders than nonresponders. We suggest that plasma olanzapine monitoring can be used for dose–response optimization, but only to complement the normal clinical evaluation process.

ISSN:0163-4356    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Levetiracetam (LEV) is a new antiepileptic drug approved as add-on therapy. Previous studies indicated that LEV has no relevant interactions with other antiepileptic drugs. The aim of this study was to investigate the influence of LEV dose, age, and co-medication on the serum concentration of LEV. In total, 363 samples of 297 inpatients who fulfilled the inclusion criteria (e.g., trough concentration, body weight available) were investigated. A patient was considered twice only if his co-medication had been changed. The LEV serum concentration in relation to LEV dose/body weight [level-to-dose ratio, LDR, (&mgr;g/mL)/(mg/kg)] was calculated and compared for the most frequent drug combinations. Analysis of covariance (using age as covariate) carried out on the log-transformed data showed that co-medication had a highly significant (P< 0.001) effect on LEV serum concentrations. The median LDR of LEV was 0.32 for LEV + phenytoin, 0.32 for LEV + carbamazepine, 0.34 LEV + oxcarbazepine, 0.45 for LEV + lamotrigine, 0.46 for LEV + phenobarital, 0.52 for LEV monotherapy, 0.53 for LEV + valproic acid, and 0.54 LEV + valproic acid + lamotrigine. In co-medication with phenytoin (P< 0.001), carbamazepine (P< 0.001), and oxcarbazepine (P< 0.004), the LDR of LEV was significantly lower than it was with LEV monotherapy, whereas the LDR of LEV of patients on co-medication with valproic acid or lamotrigine did not differ significantly from the LDR of LEV of patients on LEV monotherapy (P> 0.05). Regression analysis including all 363 samples confirmed that other drugs (e.g., phenytoin, carbamazepine) lower LEV concentrations. In addition to co-medication, age had a significant effect on clearance of LEV. Children had lower LEV concentrations than adults on the same LEV dose per body weight. In contrast to other studies, our data point out that other enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine) can moderately decrease LEV serum concentrations (by 20–30%). However, our observations should be confirmed by prospective pharmacokinetic studies.

ISSN:0163-4356    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

The influence of dosage, age, and co-medication on plasma topiramate (TPM) concentrations at steady state was investigated in 51 patients aged 3 to 30 years. All patients had chronic active epilepsy, and most were receiving concomitant medication with enzyme-inducing anticonvulsants (carbamazepine and phenobarbital). Plasma TPM concentrations were determined by a specific immunoassay in samples obtained before the morning dose. Thirty-five patients could be evaluated prospectively at different dose levels, and the relationship between plasma TPM concentration and dosage was linear over the assessed dose range (1.8 to 10.0 mg/kg) both in adults and in children. The influence of age on pharmacokinetic parameters could be assessed only for the 42 patients co-medicated with enzyme inducers. In these patients dose-normalized plasma TPM concentrations correlated positively with age (r = 0.59,P< 0.0001), where apparent oral clearance values (CL/F) were inversely related to age (r = 0.73,P< 0.0001). In particular, CL/F values in children aged less than 10 years (112 ± 82 mL/kg/h, mean ± SD, n = 14) were almost three times as high as those observed in patients aged >15 to 30 years (42 ± 16 mL/kg/h, n = 17), whereas the CL/F value in children aged 10 to 15 years (66 ± 22 mL/kg/h, n = 11) was intermediate between those found in the two other age groups. Patients not receiving enzyme-inducing AEDs showed lower CL/F values than did age- and gender-matched patients on enzyme-inducing co-medication. A preliminary evaluation of the relationship between plasma TPM concentration and therapeutic response could be made in 41 patients. No significant difference in drug concentration was detected between patients showing a greater than 50% reduction in seizure frequency compared with baseline (5.9 ± 2.2 &mgr;g/mL, n = 30) and those having no clinical improvement (5.2 ± 2.2 &mgr;g/mL, n = 11). Likewise, there was no consistent relationship between plasma TPM concentration and appearance of adverse effects. These results indicate that plasma TPM concentrations are linearly related to dosage both in adults and in children and that children aged <10 years require much greater body weight-adjusted dosage to achieve drug levels comparable to those observed in young adults. The marked increase in TPM clearance caused by enzyme-inducing co-medication was confirmed.

ISSN:0163-4356    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Therapeutic drug monitoring (TDM) services for plasma concentrations of haloperidol and bromperidol using enzyme immunoassay (EIA) methods are available in Japan, whereas high-performance liquid chromatographic (HPLC) methods are preferred in other countries. To compare these methods, we took 54 plasma samples for haloperidol and 91 plasma samples for bromperidol from schizophrenic patients receiving haloperidol or bromperidol, and the samples were measured using both commercial EIA and HPLC methods. Significant linear correlations were found between the two methods in determining haloperidol (EIA = 1.351 × HPLC + 1.39; r = 0.934,P< 0.001) and bromperidol (EIA = 1.420 × HPLC + 0.712; r = 0.956,P< 0.001) concentrations, but plasma concentrations using the EIA kits were approximately 92% (95% CI; 53–131%) and 62% (54–70%) higher than those using HPLC for haloperidol and bromperidol, respectively. Mean (and range) plasma concentrations of reduced metabolites were 54% (30–92%) and 55% (29–111%) of those of haloperidol and bromperidol, respectively. The present study suggests that reduced metabolites are included to a considerable degree in TDM data using the EIA kits. Therefore, some limitation of TDM data of haloperidol and bromperidol using the EIA kits, ie, high precision but poor accuracy, should be kept in mind.

ISSN:0163-4356    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Warfarin toxicity is common and usually results from dose changes or drug interactions. There are few reported cases of intentional overdose. The management of warfarin overdose is usually complicated by the patient using warfarin therapeutically, often for a mechanical heart valve or pulmonary embolus prophylaxis. Untreated patients have a significant bleeding risk, but treatment carries a significant risk of complete reversal of anticoagulation and consequent risk of thrombosis. The objective of this study was to describe warfarin overdoses and complications of treatment and develop a safe approach to management. Three patients are described. Two patients received a single 10-mg dose of vitamin K. Both required anticoagulation, and in one, warfarin resistance persisted for 2 weeks. In a third patient serial INR, factor levels and warfarin concentrations were measured, and incremental doses of vitamin K (up to 7.5 mg) were given based on INR. This patient did not require anticoagulation, and regular warfarin therapy was recommenced after 4 days. Patients intentionally overdosing on warfarin can be classified into three groups based on preexisting indications for warfarin: nontherapeutic, moderate risk, and major risk for thromboembolic complications. All patients should have regular INR measurements (6-hourly) to catch rapid rises. Patients not on warfarin therapeutically can be given 10 mg of vitamin K1and repeat INRs as an outpatient. Titrating intravenous vitamin K with doses of 0.5 to 2.0 mg when INR > 5 is appropriate to reduce INR without causing warfarin resistance. The high-risk group must be kept anticoagulated, and warfarin resistance avoided.

ISSN:0163-4356    

出版商:OVID    

年代:2003

数据来源: OVID