摘要:

Morphine (M) is recommended by the World Health Organization as the treatment of choice for moderate-to-severe cancer pain. Development of sensitive radioimmunoassays (RIA) and high-performance liquid chromatography in the past 20 years has allowed study of the pharmacokinetics of M, which remain incompletely understood. Data derived by RIA must be interpreted with caution due to cross-reactivity with anti-sera by metabolites, impairing assay specificity. The pharmacokinetics of M have been determined for various clinical situations, but there is large interpatient variability for most parameters. M is readily absorbed from all routes of administration, except transdermal, and it can be injected spinally. Peak plasma levels are achieved within 15–20 min of intramuscular and subcutaneous administration, and within 30–90 min after oral. Peak levels after oral administration are much lower than after parenteral routes, since oral M undergoes extensive first-pass metabolism in the liver. With repeated administration, the oral-parenteral relative potency ratio is 1:3. M can be administered epidurally or intrathecally and has also been given intracerebroventricularly. Epidural M enters the subarachnoid space, but is also absorbed into the systemic circulation. Only 5% of a dose crosses the dura. M administered in the lumbar region is quickly redistributed in the cerebrospinal fluid in a rostral direction, explaining the high incidence of systemic side effects following spinal administration. After absorption, M is rapidly and widely distributed and crosses the blood-brain barrier. With therapeutic doses, plasma protein binding is only 20–35%, and the volume of distribution is 1–6 L/kg. The primary site of M metabolism is the liver, and the dose should be reduced in patients with liver disease. Glucuronidation is the main metabolic pathway, but the principal metabolite, morphine-3-glucuronide (M3G), is inactive. Morphine-6-glucuronide (M6G) is produced in smaller amounts than M3G, but is pharmacologically active and many times more potent than M. The ratio of M6G to M in plasma, after a dose of M, is ∼10:1, and the ratio does not change with increasing doses or prolonged treatment. Normorphine (NM) is also active, and is formed to a greater extent after oral administration; it is not, however, usually found in plasma. NM may be neurotoxic. M and its metabolites are excreted by the kidney, but urinary free M accounts for

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Intracarotid drug administration after osmotic blood-brain barrier disruption (BBBD) enhances drug delivery to brain tumors. Despite clinical use, the pharmacokinetics of drugs following BBBD has not been described to date. Since methotrexate exhibits a concentration-toxicity response relationship, methotrexate disposition was determined following BBBD and intracarotid administration in seven patients with nonoperable brain tumors. Following a 1.5–5 g intracarotid methotrexate injection, 12 blood samples and 9 urine collections were obtained. Methotrexate concentrations in serum and urine were determined by fluorescence polarization immunoassay. The serum concentration-time data were best described by a three-compartment model. Systemic and renal clearances were consistent with previous studies. However, a prolonged mean terminal half-life of 51.5 h was observed. Serum methotrexate concentrations at 72 h exceeded 0.1 μmol/L in five of seven patients. Stomatitis occurred in one patient. Relative to previous reports, prolonged methotrexate half-life and cytotoxic methotrexate concentrations were observed in the serum of patients receiving intracarotid methotrexate following BBBD. Due to the prolonged cytotoxic methotrexate concentrations observed, extended leucovorin therapy may be indicated following BBBD and intracarotid methotrexate.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Thirty-five allograft recipients undergoing cyclosporine A (CsA) therapy were randomly selected to evaluate a “novel” in vitro assay that determines CsA and metabolite immunosuppressive activity in whole blood. The assay uses a third party mixed lymphocyte culture (MLC) system to which patient whole blood extracts containing CsA and metabolites are added. The ability of the extracted CsA and metabolites to inhibit proliferation in this system is proportional to the immune suppressive activity in whole blood. Comparison of the MLC suppression assay against Abbott TDx parent, TDx parent and metabolites, and radioreceptor assays utilizing cyclophilin or a 50-kDa binding protein isolated from JURKAT cytosol gave the following correlation coefficients:r= 0.612,r= 0.672,r= 0.362, andr= 0.775, respectively.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

To evaluate the reasons for the wide variability in bioavailability of orally administered 6-mercaptopurine in children with acute lymphoblastic leukemia, we studied several pharmacokinetic parameters of the drug in 18 affected children receiving remission maintenance therapy, and compared them with their anthropometric data and with the results of intestinal function tests. No correlation was found between estimates of small intestinal absorption (the oral lactose tolerance test and 1 h blood xylose test) and 6-mercaptopurine serum levels. Of the anthropometric measurements considered, only the weight/height percentile (an index of the fat body mass) strongly and linearly correlated with the area under the curve of 6-mercaptopurine. The dose of 75 mg of 6-mercaptopurine/m2of body surface resulted in higher serum concentrations in children below the 75th percentile than in those with a weight/height ratio exceeding the 75th percentile. In conclusion, these data caution about the risk of underdosing 6-mercaptopurine in overweight children when administering it on the basis of body surface area.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

Indomethacin (INDO) pharmacokinetics were examined in 18 neonates on 19 occasions, before and after patent ductus arteriosus (PDA) closure, Patients received INDO as an initial dose of 0.25 mg/kg intravenously, and INDO serum concentrations were measured 2 and 8 h after the dose. Subsequent doses were individualized based on clinical response, toxicity, and INDO pharmacokinetics. PDA status was confirmed echocardiographically at the start and end of therapy. INDO pharmacokinetic parameters varied from dose-to-dose within the same patient, and wide interpatient variability was also observed. Pre- and post-PDA closure, only INDO volume of distribution differed significantly (p< 0.001) with mean values of 0.36 (\pm0.06) L/kg and 0.26 (\pm0.08) L/kg. The reason for this occurrence remains unclear. However, a new application for pharmacokinetics as a probe of physiology is demonstrated.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

In a prospective, randomized clinical trial, we compared the accuracy of warfarin dosage-adjustments predictions using a computer program to the skill of an experienced anticoagulation nurse-specialist. The computer program predicts the steady state warfarin dose by applying Bayesian forecasting techniques to a mathematical model of the dynamic pharmacologic response to warfarin. Fifty patients who were receiving chronic warfarin therapy and who required a dosage adjustment because their prothrombin time was ≥2 s away from their target prothrombin time were enrolled. The baseline characteristics of each group were similar, including the mean of the absolute value of the differences between initial prothrombin times and corresponding target prothrombin times. After a new warfarin dose was predicted, the prothrombin time was measured at least 7 days after dosage adjustment. Overall, the results in each group were comparable. There was no significant difference between groups and the mean of the absolute value of the differences between final prothrombin times and target prothrombin times, nor was there a difference in the proportion of patients who had a final prothrombin time within 2 s of the target prothrombin time. We conclude that the accuracy of warfarin dosage adjustments made using computer modeling is comparable to the skill of an anticoagulation nurse-specialist.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

1,2-Dimethyl-3-hydroxypyridin-4-one (CP020 or L1) is a novel oral iron chelator that has proved to be effective in animals and humans. A rapid, accurate, and sensitive high-performance liquid chromatography method is described for measuring L1in human plasma using a Hypercarb 7 μm column and monitoring the column eluent by ultraviolet absorption at 280 nm. CP020 and the internal standard (CP094) were extracted into dichloromethane (2x5 ml) from plasma at neutral pH [0.25 ml of plasma + 0.75 ml of 60 mM3-(N-morpholino)propanesulfonic acid buffer, pH 7.4]. The method proved to be linear (r2= 0.998) in the clinical range of 0.5–50 μg/ml when 0.25 ml of plasma was used, with the coefficient of variation less than 10% even at the lower concentration range.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

We compared three chromatographic methods for the therapeutic control of clonazepam. The first method analyzes the underivatized benzodiazepine, direct gas chromatography (GC) method, using nitrazepam as internal standard and GC with an electron-capture detector (63Ni). This method was compared with a second one, in which the same compounds were converted to the respective methylated derivatives (GC of derivatized samples) and also quantified by GC. The two methods were then compared with a third procedure for clonazepam quantification, using high-performance liquid chromatography (HPLC). Statistical analysis of clonazepam concentrations detected in the plasma of 37 patients, treated with Rivotril, indicated that HPLC is the most precise method, showed just significant correlations among the three methods, and suggested that plasma concentrations of clonazepam, estimated by the direct GC method, are significantly lower than those determined by the other two methods. The direct GC method and HPLC have been proposed as reference methods for the therapeutic control of clonazepam, with options for use left to the resources available in various laboratories.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

A rapid, accurate, and sensitive high-performance liquid chromatographic (HPLC) method, with ultraviolet detection, for simultaneous measurement of halofantrine (HAL) and desbutylhalofantrine (BHAL) in human serum is described. Sample preparation involved protein precipitation, followed by a solid-phase clean-up and a liquid-liquid extraction. Chromatographic separation was carried out on an Ultrasphere C8 column (25 cm x 4.6 mm I.D., 5 μm particle size) using a mobile phase of acetonitrile:water, 75:25, (vol/vol), with 0.2% (w/vol) sodium dodecyl sulfate and 0.2% (vol/vol) glacial acetic acid. The serum sample volume used was 0.5 ml, with concentrations normalized to 1 ml. Retention times for BHAL, HAL, and the internal standard were 5.5, 8.3, and 11.5 min, respectively, with a total run time of 13.5 min. The average extraction recovery for HAL was 85.6% and 100.5% for BHAL. Inter- and intra-assay precisions of HAL and BHAL were $7.5%, with an accuracy of $10.8% over three concentrations (0.02, 0.5, 2.0 μg/ml). Detection limits of HAL and BHAL were 5 and 3 ng/ml, respectively. The new HPLC method resulted in cleaner chromatograms and a 1.7-fold faster run time than previous HPLC methods. Application of the method with clinical specimens was demonstrated.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

A high performance liquid chromatographic method for the simultaneous quantitation of clozapinea member of the dibenzodiazepine class of antipsychotic drugsand its reduced metabolite in human plasma has been developed. Clozapine andN-desmethylclozapine are concentrated from blood samples by liquid-liquid extraction, followed by reverse-phase liquid chromatography. Accuracy of the determination is ensured by application of an internal standard, protriptyline, which is closely related to clozapine. A detection limit of 15 ng/mL for clozapine and 30 ng/ml forN-desmethylclozapine was achieved.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID