摘要:

Clinical Pharmacology and Therapeutics(1993)53,1–2; doi:10.1038/clpt.1993

ISSN:0009-9236    

DOI:10.1038/clpt.1993.1

年代:1993

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1993)53,3–5; doi:10.1038/clpt.1993

ISSN:0009-9236    

DOI:10.1038/clpt.1993.2

年代:1993

数据来源: WILEY

摘要:

We propose a parametric pharmacokinetic‐pharmacodynamic model for caffeine that quantifies the development of tolerance to the pressor effect of the drug and characterizes the mean behavior and inter‐individual variation of both pharmacokinetics and pressor effect. Our study in a small group of subjects indicates that acute tolerance develops to the pressor effect of caffeine and that both the pressor effect and tolerance occur after some time delay relative to changes in plasma caffeine concentration. The half‐life of equilibration of effect with plasma caffeine concentration is about 20 minutes. The half‐life of development and regression of tolerance is estimated to be about 1 hour, and the model suggests that tolerance, at its fullest, causes more than a 90% reduction of initial (nontolerant) effect. Whereas tolerance to the pressor effect of caffeine develops in habitual coffee drinkers, the pressor response is regained after relatively brief periods of abstinence. Because of the rapid development and regression of tolerance, the pressor response to caffeine depends on how much caffeine is consumed, the schedule of consumption, and the elimination half‐life of caffeine.Clinical Pharmacology and Therapeutics(1993)53,6–14; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1993.3

年代:1993

数据来源: WILEY

摘要:

The pharmacokinetic characteristics of ganciclovir were determined in neonates (age range, 2 to 49 days) after an 1‐hour intravenous infusion of a single dose of either 4 mg/kg(n =14) or 6 mg/kg(n= 13). Twenty‐seven newborns with symptomatic cytomegalovirus inclusion disease were enrolled in this open phase I‐II pharmacokinetics, safety, and tolerance trial of ganciclovir at one of two doses. Ganciclovir disposition was best described by a one‐compartment open model with zero‐order input and first‐order elimination. The mean elimination half‐life (t½) for both dose groups was 2.4 hours. The mean apparent volume of distribution (Vd) was 669 ± 70 ml/kg for the 4 mg/kg group and 749 ± 59 ml/kg for the 6 mg/kg group. The mean total body clearance (CL) for the 4 mg/kg and 6 mg/kg groups was 189 ± 28 ml/hr/kg and 213 ± 21 ml/hr/kg, respectively. No significant differences were observed in Vd or CL between the two groups. The Vd, expressed in milliliters, increased with increasing patient weight(r= 0.689;p= 0.0001). The CL, expressed in milliliters per hour per kilogram, increased with increasing age(r= 0.413;p =0.032). No significant differences were observed between the two dose groups for the area under the curve normalized for dose (AUC/Dose) or the maximum plasma concentration normalized for dose (Cmax/Dose), indicating that ganciclovir exhibited linear pharmacokinetics in these neonates.Clinical Pharmacology and Therapeutics(1993)53,15–21; do

ISSN:0009-9236    

DOI:10.1038/clpt.1993.4

年代:1993

数据来源: WILEY

摘要:

Pharmacokinetic data from 48 children who were taking valproic acid were analyzed by multiple step‐wise linear regression. Children who were receiving enzyme‐inducing antiepileptic drugs(n= 27) had greater(p<0.01) clearances, elimination rates, and dosage requirements and greater(p<0.05) variability in pharmacokinetic values than patients receiving monotherapy. Age and polytherapy explained most of the interpatient variability in total (r2= 0.80;p<0.001) and intrinsic (r2= 0.77;p<0.001) clearances and the elimination rate (r2= 0.61;p<0.002). Free fraction variability was related to valproate concentration and phenobarbital (r2= 0.47;p<0.001). Distribution volume variance was associated with free fraction (r2= 0.48;p<0.001). The effect of age and polytherapy on valproate clearance is primarily attributable to changes in metabolism rather than in protein binding. Valproic acid dosage requirements are greater and more variable for children who are receiving other enzyme‐inducing antiepileptic drugs.Clinical Pharmacology and Therapeutics(1993)53,22–29; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1993.5

年代:1993

数据来源: WILEY

摘要:

In a previously reported clinical trial, patients with Alzheimer's disease were treated with deferoxamine mesylate, which resulted in a 50% reduction in the average rate of deterioration over 2 years. There were five deaths in the untreated group during the trial and no deaths in the treated group, although five of 25 treated patients reported anorexia. Deferoxamine metabolite analysis of urine for 24 hours after deferoxamine injection from sensitive and nonsensitive patients showed marked differences. Occurrence of side effects correlated with increased formation of a monoamine oxidase catalyzed (major) metabolite, MFO1. The metabolite ratio, MFO1/total metabolites, plus parent drug (TOT) showed a bimodal distribution with a mean ± SD value of 0.68 ± 0.06 for the nonsensitive and 0.79 ± 0.04 for sensitive patients. The MFO1/TOT ratio discriminates between sensitive and nonsensitive patients, and we suggest that the half difference mark between the two mean values (0.735) can be used as a predictor of side effects. Patients with a MFO1/TOT ratio of greater than 0.70 would be considered at risk and observed for onset of side effects. Patients with a MFO1/TOT ratio greater than 0.80 would be considered for immediate adjunct treatment with isoniazid or other monoamine oxidase inhibitors.Clinical Pharmacology and Therapeutics(1993)53,30–37; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1993.6

年代:1993

数据来源: WILEY

摘要:

Although propafenone is a known substrate and inhibitor of the cytochrome P450 4‐hydroxylation pathway of debrisoquin (CYP2D6 isozyme), its effects on other hepatic mixed‐ function oxidative isozymes have not been extensively evaluated. We studied the influence of propafenone on the disposition of continuously infused lidocaine in 12 healthy male volunteers. Placebo or propafenone (225 mg every 8 hours) was orally administered for 4 days before and during lidocaine administration (2 mg/kg/hr for 22 hours). In the 11 (92%) subjects phenotyped as extensive metabolizers, propafenone significantly increased the lidocaine area under the plasma concentration time curve (81.7 ± 16.2 versus 76.3 ± 15.6 µg · hr/ml;p≤ 0.05) and reduced systemic lidocaine clearance (9.53 ± 1.77 versus 10.27 ± 2.24 ml/min/kg;p≤ 0.05), but did not significantly affect volume of distribution at steady state (2.48 ± 0.33 versus 2.64 ± 0.45 L/kg;p= 0.10) or mean residence time (4.37 ± 0.92 versus 4.47 ± 0.87 hours; difference not significant) compared with placebo, respectively. Adverse central nervous system effects were significantly worse in severity and duration during the propafenone phase(p≤ 0.05). Propafenone minimally inhibits the metabolism of lidocaine. This suggests that the ability of propafenone to inhibit metabolic pathways exclusive of the CYP2D6 isozyme may be limited. In addition, potentiation of disturbing central nervous system adverse effects may occur during combination therapy of propafenone and lidocaine.Clinical Pharmacology and Therapeutics(1993)53,38–48; d

ISSN:0009-9236    

DOI:10.1038/clpt.1993.7

年代:1993

数据来源: WILEY

摘要:

Characterization of glutathione conjugation in vivo was performed in 12 healthy male volunteers by use of the racemic drug bromisovalum (bromisoval; 2‐bromoisovalerylurea) as a model substrate. To study whether the pharmacokinetics of both bromisovalum enantiomers was related to the glutathioneS‐transferase class Mu phenotype, six subjects who were class Mu deficient and six subjects who were not class Mu deficient participated. After oral administration of 600 mg racemic bromisovalum, enantioselective measurement of unchanged bromisovalum (plasma and saliva) and the diastereomeric bromisovalum mercapturates (urine) showed a pronounced stereoselectivity in all subjects. The plasma clearance ofR‐bromisovalum was about 12 times higher than that ofS‐bromisovalum (9.3 ± 3.7 and 0.78 ± 0.38 L/min, respectively), which was in agreement with the higher urinary cumulative excretion for the mercapturate derived fromR‐bromisovalum: 26% ± 4% of the dose versus 8% ± 3% of the dose for the mercapturate derived fromS‐bromisovalum. Both the bromisovalum pharmacokinetics in general and the stereoselectivity in bromisovalum pharmacokinetics were not different for the subjects who were glutathioneS‐transferase class Mu deficient and the subjects who were not glutathione transferase class Mu deficient.Clinical Pharmacology and Therapeutics(1993)53,49–58; doi

ISSN:0009-9236    

DOI:10.1038/clpt.1993.8

年代:1993

数据来源: WILEY

摘要:

The effect of flecainide on the QRS interval was studied in 10 patients who were receiving long‐term oral treatment (50 to 150 mg twice daily) for arrhythmias that were refractory to other drugs. Total and free drug plasma levels and QRS durations were measured at intervals after the morning administration. Free drug plasma levels were linearly correlated with QRS duration in each patient and the slope of the line was widely variable in the population studied. Even after the data from one patient with an unusually high slope (0.454) was excluded from the analysis, the slope range was 0.0284 to 0.144. Pharmacodynamic variability could not be explained by heart rate changes, active metabolites, electrolyte disturbances, or free drug concentration. None of the pharmacokinetic parameters measured (average steady‐state concentration, fluctuation of maximum and minimum concentrations, time to peak concentration, final half‐life, and protein binding) showed an intersubject variability greater than 4.4 times. Our findings suggest that the determination of flecainide free plasma concentration may not be sufficient to forecast electrophysiologic effects in individual patients.Clinical Pharmacology and Therapeutics(1993)53,59–64; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1993.9

年代:1993

数据来源: WILEY

摘要:

The efficacy and acceptability of two widely used oral contraceptive tablets, one containing 250 mg levonorgestrel and 50 µg ethinyl estradiol and the other containing 150 μg desogestrel and 30 µg ethinyl estradiol, administered by the vaginal route were compared in 1055 women studied over 12,630 woman‐months of vaginal contraceptive pill use. This multicenter clinical trial was performed in nine countries of the developing world by the “South to South Cooperation in Reproductive Health,” an organization founded by scientists from the Third World working in the area of reproductive health, and the study was developed and coordinated by one of these centers. The findings of this study confirm the efficacy of both these tablets when administered by the vaginal route. Involuntary pregnancy rates at 1 year of 2.78 for subjects in the levonorgestrel group and 4.54 for subjects the desogestrel group showed no statistically significant difference between the two groups. However, total discontinuation rates of 47.01 for subjects in the levonorgestrel group and 56.33 for subjects in the desogestrel group showed a statistically significant difference between the two groups, and discontinuation rates attributable to prolonged bleeding of 0.6 for subjects in the levonorgestrel group and 3.2 for subjects in the desogestrel group were also significantly higher in the group of subjects using the desogestrel vaginal contraceptive pill. Blood pressure remained at admission values throughout treatment. A statistically significant weight increase from admission values occurred in both groups of subjects.Clinical Pharmacology and Therapeutics(1993)53,65–75; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1993.10

年代:1993

数据来源: WILEY