摘要:

SummarySeven cyclosporin G metabolites were isolated by high-performance liquid chromatography from the urine of normal subjects receiving the drug. The structure and purity of the metabolites were assessed by fast atom bombardment/mass spectroscopy, by proton nuclear magnetic resonance (NMR), and by13C-NMR. The structural modifications of the cyclosporin G metabolites consisted primarily of hydroxylation and demethylation, as is the case for cyclosporin A metabolites. The immunosuppressive activities of the metabolites were tested in three separate in vitro systems: a primary and secondary mixed lymphocyte system, as well as a mitogen stimulated system. In general, the metabolites have immunosuppressive activity of

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryCyclosporine A (CsA) is a very lipophilic, immunosuppressive peptide that is highly bound (>95%) in plasma. Approximately 50% of the drug is bound to lipoproteins and the remainder to erythrocytes. Neither the therapeutic nor the toxic effects of cyclosporine have been correlated with the free drug concentration. It has been proposed that low-density lipoprotein (LDL) delivers CsA to T-lymphocytes via the LDL receptor pathway, where it then produces its therapeutic effects. We have found that our patients chronically treated with cyclosporine carry as much or more CsA in very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and high-density lipoprotein (HDL) as they do in LDL. In addition, as previously reported, those patients with high VLDL carried the major portion of CsA in their VLDL subfraction. Moreover, the triglyceride-rich lipoproteins (VLDL and IDL) were found to contain much more CsA per mg of lipid than either HDL or LDL. An acute drug challenge led to the same CsA distribution as that seen in the chronically treated patients. “In vitro” incubations of lipoproteins containing CsA with lipoproteins from untreated individuals demonstrated a different relative affinity of CsA for the various lipoproteins than would be predicted from the plasma distribution: LDL > VLDL > HDL. We propose that the plasma distribution of CsA is determined by factors other than simple diffusion between the lipoprotein particles. Possible mechanisms would include (a) plasma factors that augment or inhibit CsA transfer or (b) metabolic processing of the lipoproteins that move CsA from one lipoprotein to another.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryThe effect of plasma exchange (PE) on the pharmacokinetics of flumequine (Apurone) was studied in eight patients receiving a single oral dose of 800 mg. The maximum concentration (38 μg/ml) and time to maximum concentration (2.6 h) values were not significantly altered by PE beginning 3 h after administration of flumequine. There was no change in the terminal elimination half-lives (6.6 h), in the steady-state volume of distribution (29 L), or in the apparent plasma clearances (2.5 L/h). By contrast, PE decreased the mean residence time by 30% (14.3 ± 4.1 h without PE; 9.88 ± 1.36 h with PE;p<0.05). The amount of flumequine extracted by PE (72 mg) was proportional to the plasma concentration at the beginning of the exchange. The elimination half-life during PE (3.15 ± 1.23 h) decreased by 40%. Renal clearance (0.3 L/h) was not affected. PE only partially modifies the pharmacokinetics of flumequine administered in a single oral dose before PE.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryTo help clarify whether food or enteral nutrients decrease hydralazine relative bioavailability, eight subjects were given oral hydralazine under four nutritional conditions: fasted (F), with a standard breakfast (SB), with a bolus of enteral nutrients (EB), and with a slow infusion of enteral nutrients administered by nasogastric tube (EI). The area under the curve and maximum concentration values were much higher under the fasted and enteral infusion conditions than under the standard breakfast or enteral bolus conditions, indicating that the absorption and/or disposition kinetics of hydralazine may be altered by food. The median (range) values for these parameters were 2,641 (385–4,747) and 87 (4.5–224) for F; 1,189 (202–1,737) and 15 (3.5–33.9) for SB; 999 (227–3,576) and 11 (2.5–50) for EB; and 3,068 (313–4,917) ng/ml/min and 113 (3.6–235) ng/ml for EI. Furthermore, the rate of nutrient administration, but not necessarily the physical form, of the nutrients appears to be a significant factor in determining the magnitude of the food effect. The nutrient interaction should be accounted for in patients receiving hydralazine and enteral nutrition concomitantly.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryAdolescents frequently require medication for acute and chronic illnesses. A proper dosage schedule is needed to achieve efficacy without toxicity during adolescence when there are marked changes in body size and organ function. Theophylline disposition was studied in 70 asthmatic adolescents, ages 8–18 years, to determine if pubertal changes in body size, composition, and organ function are associated with changes in drug disposition. Forty-eight youngsters were studied as outpatients and 22 while hospitalized. Half-life (t1/2) was computed for all patients. Volume of distribution and clearance were determined for inpatients only. Chronological age and anthropometric growth parameters were measured. Lean body mass (LBM) was derived from anthropometric measurements. Half-life was significantly correlated with developmental stage (Tannerr= 0.42, ager= 0.33,p<0.01), and body size (heightr= 0.39, LBMr= 0.33, weightr= 0.33,p<0.01). LBM (kg/kg) was significantly correlated with volume of distribution (L/kg) (r= 0.59,p<0.01). Best-fits fort1/2contained two variables:t1/2= – 4.57 + 1.31 (sex) + 0.0687 (height) (r= 0.48) andt1/2= – 3.54 + 1.32 (sex) + 0.0725 (LBM) (r= 0.43). Chronological age alone is not a useful basis for determining medication dosages due to the heterogeneity in rates of development and body size among adolescents. Half-life increases with increasing height or LBM. Although compliance is clearly an important factor in achieving optimal control of symptoms, this study demonstrates that dose adjustment during times of rapid growth during puberty is equally important.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummarySteady-state plasma valproic acid (VPA) concentrations were measured in 118 pediatric inpatients taking VPA. There was a significant (p<0.0001) inverse correlation between the daily VPA dosage and the VPA dose ratio (concentration/dose or 1/clearance). The VPA dose ratio was significantly lower in patients taking VPA in combination with phenobarbital (p<0.01), carbamazepine (p<0.05), or multiple other antiepileptic drugs (p<0.0001), compared with those on VPA monotherapy. Neither age nor sex had any influence on VPA dose ratios. No significant (p> 0.1) correlation was found between VPA doses and concentrations in children on monotherapy. The distribution of VPA dose concentrations suggests that children, especially those on VPA polytherapy, require higher than recommended pediatric VPA maintenance doses (>60 mg/kg/day) to maintain concentrations >50 mg/L. Results also indicate that at higher concentrations (>80 mg/L), increasing doses may produce less than proportional increases in total VPA concentration.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryA retrospective analysis of Veterans Administration (VA) Cooperative Study No. 118 was conducted to examine the relationship between serum phenytoin concentration (SPC) and various measures of patient response in 111 patients on monotherapy, mostly after 12 months of treatment. Using patient response rating scales specifically developed and validated for the VA study, we plotted SPC vs overall composite score as well as vs each of the three component ratings of neurotoxicity, systemic toxicity, and seizure type and frequency. No statistically significant association was noted between SPC and any of the response measures. We also calculated test performance characteristics for using SPC and a therapeutic range of 10–22 μg/ml to categorize patient status with regard to overall response, toxicity, and seizure frequency. Test sensitivities (0.13–0.53), specificities (0.62–0.81), and positive predictive values (0.08–0.44) were much lower than desirable. This results in a large proportion of false-positive and false-negative errors associated with the use of SPC as a test. Our retrospective evaluation suggests that the range of SPC values in successfully treated patients is quite broad; the value of the commonly accepted SPC therapeutic range in predicting various measures of patient response is quite limited; and patient response, therefore, should be the ultimate end point in monitoring patients on phenytoin. Prospective studies of the relationship between SPC and response should be conducted.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryZidovudine (ZDV) elicits its antiviral effect through intracellular metabolism to the 5‘-triphosphate, which interferes with viral replication. Monitoring of the active metabolites of ZDV in cells could lead to an intracellular therapeutic range. This study was performed to determine whether a radioimmunoassay, previously used for in vitro quantitation of total phosphorylated ZDV inside peripheral blood leukocytes, could be used for similar determinations in patient samples. The relationship between ZDV dose, plasma concentrations, and intracellular metabolite concentrations was also examined. Ten-milliliter blood samples were drawn from each of 13 human immunodeficiency virus-infected patients and were assayed. Intracellular concentrations of phosphorylated ZDV ranged from 0.33 to 3.54 pmol/106cells, similar to those observed in vitro. Phosphorylated ZDV was independent of dose, and did not correlate with plasma concentrations. Intracellular concentration in the patient population as a whole did not change during the 4-h dosing interval, while plasma concentration decayed normally. Later determinations in the same patients gave intracellular values within 31% of earlier values. Intraassay variability was less than 10%. Thus, the method is valid for measurement of phosphorylated ZDV in patient cells. Although individual concentrations showed no clear change during the 3-month study period, intracellular concentrations decreased with increasing length of therapy (up to 3 years) in the population as a whole. This suggests a decreased cellular ability to phosphorylate ZDV after prolonged exposure to drug. The lack of intracellular decay implies a half-life longer than the 1-h half-life of plasma ZDV. These data suggest that smaller doses or longer dosing intervals might maintain intracellular concentrations once steady state is achieved. With no relationship to concentrations of phosphorylated ZDV, plasma concentrations are likely to be of limited value for therapeutic monitoring of this drug.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryA stereospecific high-performance liquid chromatographic assay for the enantiomers of phenylpropanolamine (PPA) in human plasma has been developed. The method is based on reaction of extracted PPA with the chiral derivatizing agent 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate to form diastereomeric thiourea derivatives. These thiourea derivatives are stable for at least 24 h, readily separable by reversed-phase chromatography, and amenable to ultraviolet detection at 254 nm. Standard curves for each of the PPA enantiomers are linear over the concentration range 10–250 μg/L. Over the approximate range of the standard curve, precision (intra- and interday) ranged from 2.2–7.0% while accuracy ranged from 99.2–107.3%. The method has been shown to be free from interference from endogenous plasma constituents and from a range of drugs containing a primary or secondary amine function. Individual PPA enantiomer plasma concentration-time profiles measured for a subject administered racemic PPA are included to demonstrate the utility of the assay.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID

摘要:

SummaryThe analysis of clobazam and its metabolite desmethylclobazam by high-performance liquid chromatography is described. After adding an internal standard 500 μl of plasma is extracted under basic conditions into dichloroethane. The organic solvent is then evaporated to dryness and the residue reconstituted in 100 μl of mobile phase prior to injecting an aliquot (30 μl) onto a Hypersil 5 MOS column, which is eluted with acetonitrile/acetate buffer (pH 5.4) 40:60 vol/vol. The components are separated in approximately 12 min. Using this method, 15 μ L−1of clobazam and 30 μ L−1of desmethylclobazam can be detected. The method is suitable for the therapeutic monitoring of these two drugs in patient samples.

ISSN:0163-4356    

出版商:OVID    

年代:1991

数据来源: OVID