摘要:

SummaryWe measured citalopram and desmethylcitalopram concentrations in serum from 169 psychiatric patients, who were treated with common therapeutic drug doses. Altogether 202 serum samples were assayed by a nonenantioselective high-performance liquid chromatography (HPLC) method. The results indicate that the kinetic variability (maximum concentration/minimum concentration) in dose- and weight-related serum citalopram (10.6-fold) and desmethylcitalopram (7.2-fold) is large even during monotherapy. Log serum citalopram (r= 0.36,p< 0.05) and desmethylcitalopram (r= 0.51,p< 0.01) concentrations of individual patients increased significantly with increasing drug doses. Dose- and weight-related (calculated as mg/kg dose basis) log serum citalopram (r= 0.29) but not desmethylcitalopram (r= 0.06) concentrations increased with aging (p< 0.001). No sex-related differences were found. Nineteen patients (19 samples) had concomitant treatment with neuroleptics, 84 patients (101 samples) with benzodiazepines, and 18 patients (28 samples) with tricyclic antidepressants. The concentrations in these patients were compared with those of 48 nonsmoking patients (54 samples) without any concomitant psychotropic drug treatment. None of the single neuroleptics alone had a significant effect on dose- and weight-related serum citalopram or desmethylcitalopram concentrations. However, citalopram concentrations increased by 121% (338 ± 165 vs. 747 ± 505, mean ± SD;p< 0.01) and desmethylcitalopram by 85% (124 ± 53 vs. 229 ± 138;p< 0.05) when neuroleptics were pooled. Among single benzodiazepines, only alprazolam increased serum citalopram (338 ± 165 vs. 391 ± 267;p< 0.01) and desmethylcitalopram (124 ± 53 vs. 186 ± 175;p< 0.01) concentrations. When all the benzodiazepines were pooled, they still increased the serum concentration of the parent drug by 23% (338 ± 165 vs. 414 ± 303;p< 0.05) and those of the metabolite by 47% (124 ± 53 vs. 182 ± 163;p< 0.01). In patients who were simultaneously treated with clomipramine, serum citalopram (338 ± 165 vs. 655 ± 409;p< 0.001) and desmethylcitalopram (124 ± 53 vs. 435 ± 347;p< 0.001) concentrations were consistently higher than those of the controls. Even when the tricyclic antidepressants were pooled, they increased citalopram concentrations by 44% (338 ± 165 vs. 486 ± 312;p< 0.001) and desmethylcitalopram concentrations by 111% (124 ± 53 vs. 261 ± 260;p< 0.001). The results suggest that interindividual variability in serum citalopram concentrations is pronounced and that increased serum citalopram levels are related to advancing age and concomitant treatment with other psychotropic drugs. The citalopram dose should therefore ideally be individualized by therapeutic drug monitoring.

ISSN:0163-4356    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

SummaryThe predictive performance of a new algorithm to calculate the initial daily dose of tobramycin in patients with cystic fibrosis (CF) was prospectively evaluated. Twenty-six patients with CF (15 men, 11 women, 18-45 years of age) with an acute exacerbation of their chronic pulmonary infection were treated with intravenous tobramycin. The initial dose was calculated with a previously presented algorithm. This algorithm was derived from correlation analysis performed on the adjusted daily dose guided by the determination of serum concentrations: dose (mg three times daily) = 90 + 2.13 × LBM (kg), where LBM (male) = (1.1 × body weight [BW]) - (128 × BW2/height2) and LBM (female) = (1.07 × BW) - (148 × BW2/height2). The predictive performance of this algorithm was evaluated comparing the calculated initial daily dose with the adjusted daily dose for peak and trough levels of 9-11 mg/L and 1.0 mg/L, respectively. Mean squared error and mean error were determined as reflections of precision and bias. The predictive performance of the algorithm was compared with historical data on the predictive performance of the standard equation to dose of 3.3 mg/kg body weight three times daily. The dose calculated with the algorithm proved to give peak serum concentrations in a narrower range and to have a greater precision, but bias was equal. Applying the algorithm, more patients had initial peak serum concentrations in the predetermined range of 9-11 mg/L than when using the standard equation, so fewer dose adjustments had to be made.

ISSN:0163-4356    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

SummaryThe azole antimycotics itraconazole and ketoconazole are potent and relatively nonspecific inhibitors of cytochrome P450 enzymes and have a potentially dangerous interaction with midazolam and triazolam. The possible interaction between itraconazole and a short-acting benzodiazepine, temazepam, was investigated in a double-blind, randomized crossover study. Ten healthy volunteers were given placebo or 200 mg itraconazole a day orally for 4 days. The challenge dose of 20 mg of temazepam was ingested on the fourth day, after which plasma samples were collected, and psychomotor performance tests were carried out for 24 h. Despite a statistically significant small increase of the area under the temazepam concentration-time curve, there was no clinically significant interaction, as determined by the psychomotor performance tests. The different metabolic pathways and the lack of significant first-pass metabolism of temazepam explain the great difference in the interaction potential of temazepam compared with midazolam and triazolam. Temazepam, unlike midazolam and triazolam, can be prescribed in usual doses for patients receiving itraconazole and other inhibitors of P450 3A4.

ISSN:0163-4356    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

SummaryThe pharmacokinetics of total and free methotrexate (MTX) were investigated in 50 patients with rheumatoid arthritis. Each patient received 10 mg MTX intramuscularly. The free and total plasma concentrations of MTX were measured over a 36-h period after drug administration by using the Abbott TDx fluorescence polarization immunoassay. Plasma concentrations of MTX were described by a biexponential function. The mean terminal elimination half-lives of total and free MTX were 9.4 and 8.4 h, respectively, and the corresponding mean residence times, 8.5 and 9.2 h. No difference in these parameters was found by comparing total and free MTX. Total plasma clearance of the free fraction averaged 215 ml/min. The statistical comparison of the variations with time of the ratio of free to total MTX during the 36 h after the dose showed that the free fraction was significantly increased for 8 h after drug administration (p< 0.001). To describe these variations, the changes of the free MTX concentrations (unbound) were related to the changes of the total MTX concentrations by using the Hill equation. Mean plasma protein binding ranged from 20 to 57% for these patients.

ISSN:0163-4356    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

SummaryThe concentration-time profiles of metabolites of moxisylyte (or thymoxamine), an α-blocking agent, were investigated in 18 healthy volunteers after intravenous (i.v.) and intracavernous (i.c.) administrations with and without a tourniquet. Four metabolites, unconjugated desacetylmoxisylyte (DAM), DAM glucuronide, and DAM and monodesmethylated DAM (MDAM) sulfates, were found in plasma and urine. For all metabolites,tmaxwas significantly increased after i.c. administrations andCmaxwas significantly decreased. Maximum plasma level of unconjugated DAM was lower after i.c. administration with (1.81-fold) and without (1.26-fold) a tourniquet than after i.v. administration (43.6 ± 19.6 ng/ml). The elimination half-life of each metabolite showed no change between the three treatments. The difference of 19 min between the mean residence times of unconjugated DAM after i.c. administration with and without a tourniquet may be compared with the difference between the mean duration of the intumescence, that is, 19 min (73 and 54 min with and without a tourniquet, respectively). Total percentages of metabolites recovered in urine were 66.2 ± 20.9, 61.4 ± 12.2, and 58.7 ± 9.1% after i.v. and i.c. administrations with and without a tourniquet, respectively. In conclusion, tourniquet placed before i.c. administration increased the mean residence time of unconjugated DAM of ≈25% and seemed to increase the efficacy of the drug in healthy volunteers.

ISSN:0163-4356    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

SummaryThe aim of this study was to adapt the vacomycin therapeutic range to the kinetic models usually employed in clinical settings (one- and two-compartment models). Estimates of vancomycin pharmacokinetic parameters were obtained for both models in 22 hematologically malignant patients on vancomycin treatment using two serum concentrations and a bayesian algorithm. From these individually estimated pharmacokinetic parameters, an estimation of the maximum (Cmaxss), 2 h postinfusion (C2ss), and minimum (Cminss) steady-state vancomycin serum concentrations for the one- and two-compartment models was made for a fixed 30 mg/kg/day dose. The linear regression equations between the predicted C2ssand Cminssfor the one- and two-compartment models do not differ significantly from the identity line, whereas the corresponding equation for Cmaxsspoints to a 61% underestimation of Cmaxsswhen the one-compartment model is used. From this latter regression equation, it is possible to define 20 mg/L (range of 18-21 mg/L) as a target Cmaxssvancomycin serum concentration when a one-compartment model is used to monitor vancomycin therapy. Another practical approach would be to define the target concentration by a desired range at 2 h, which corresponds to a Cmaxssvalue of 30-40 mg/L.

ISSN:0163-4356    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

SummaryUsing data gathered in routine monitoring, the pharmacokinetics of vancomycin during the first 10 days of treatment were compared with the pharmacokinetics after 10 days of treatment in 46 adult patients with normal renal function, ages 17-85 years old (mean ± SD: 50.8 ± 17.5). The mean time from initiation of treatment to the first sample determination was 5.5 days, and the mean time to the second determination was 13.4 days. Statistical differences between the two periods were observed for all pharmacokinetic parameters, except for the steady-state distribution volume. After 10 days of treatment, the mean ± SD of the vancomycin clearance and elimination rate constant decreased from 1.31 ± 0.82 to 1.13 ± 0.72 ml/kg/min (p = 0.0044) and from 0.13 ± 0.08 to 0.10 ± 0.06 h-1(p = 0.091), respectively. The half-life (t½) increased from 8.01 ± 6.82 to 10.02 ± 8.00 h (p = 0.012). The median percentage of the increment of t½was 9.4%. The increase in t½was >50% in 12 patients and >100% in nine cases. No association was found between the increment of t½and the cumulative vancomycin dose. Frequent monitoring of serum vancomycin seems indicated, given the risk of decreased elimination during prolonged treatment.

ISSN:0163-4356    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

SummaryAn isocratic high performance liquid chromatographic micromethod is described for the quantitation of levetiracetam (ucb LO59) in plasma or serum of patients. The chromatography is performed on a 250 × 4 mm I.D. LiChrospher 60 RP-select B, 5-μm column, eluted with an acetonitrile/50 mMphosphate buffer (15:85 vol/vol, pH 5.6) mobile phase, and levetiracetam detected using ultraviolet absorbance at 220 nm. The limit of quantitation was 5 μmol/L and the within-batch and between-batch coefficients of variation were <7%. No interference from commonly prescribed antiepileptic drugs (carbamazepine and its metabolite carbamazepine epoxide, ethosuximide, gabapentin, lamotrigine, phenobarbitone, phenytoin, primidone, valproic acid, and vigabatrin) was observed, and thus the method can be used to monitor levetiracetam in patients on polytherapy antiepileptic drug regimens.

ISSN:0163-4356    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

SummaryA high-performance liquid chromatographic (HPLC) method is described for the simultaneous determination of a fluoroquinolone, pefloxacin, and its main active metabolite norfloxacin (N-desmethyl metabolite) in serum. Sample preparation involves protein precipitation with acetonitrile. The drugs and the internal standard (acebutolol) were eluted from a 4-μm Novapak C-18 cartridge at ambient temperature with an isocratic mobile phase consisting of 14% acetonitrile in buffer solution, at a flow rate of 2.5 ml/min. The effluent was monitored on a fluorescence detector using excitation and emission wavelengths of 330 and 440 nm, respectively. Each analysis required no longer than 8 min. Quantification was achieved by measurement of the peak-area ratio of the drugs to the internal standard, and the limit of quantification for both pefloxacin and norfloxacin in serum was 50 ng/ml. The intraday coefficient of variation (CV) ranged from 1.3 to 4.4% and from 2.2 to 7.5% for pefloxacin and norfloxacin, respectively, at the concentration ranges evaluated. The interday CV ranged from 1.1 to 5.9% and from 2.3 to 5.6% for pefloxacin and norfloxacin, respectively, at three concentrations. Relative recovery was 105.5 and 99.5% for pefloxacin and norfloxacin, respectively. Stability tests show that pefloxacin and norfloxacin are stable in serum for at least 3 weeks when stored at -20°C. This method has been used successfully in pharmacokinetic studies in humans.

ISSN:0163-4356    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

SummaryEffects of carbamazepine coadministration on plasma concentrations of trazodone and its active metabolite,m-chlorophenylpiperazine (m-CPP) were studied in six depressed patients treated with trazodone. The daily dose of trazodone was 150 mg in three cases and 300 mg in three cases. Carbamazepine, 400 mg/day, was coadministered for 4 weeks, and blood samples were taken before carbamazepine addition and at weekly intervals after the addition. Carbamazepine significantly (p< 0.01) decreased plasma concentrations of not only trazodone but also m-CPP at each week. On the average, plasma concentrations of trazodone and m-CPP at 4 weeks were 24 and 40% of the corresponding precarbamazepine values. This study thus suggests that carbamazepine coadministration decreases plasma concentrations of trazodone and m-CPP by inducing the metabolism of these compounds.

ISSN:0163-4356    

出版商:OVID    

年代:1996

数据来源: OVID