摘要:

Clinical Pharmacology and Therapeutics(1994)55, 609–622; doi:10.1038/clpt.1994.

ISSN:0009-9236    

DOI:10.1038/clpt.1994.78

年代:1994

数据来源: WILEY

摘要:

The influence of interoccasion variability in clearance on bioavailability estimates from a traditional two‐period crossover design is reported for five methods of analysis: (1) the standard crossover analysis, (2) a groupwise, parallel, analysis, (3) and (4) two correction procedures suggested by J. G. Wagner and by P. S. Collier and S. Riegelman, and (5) a pharmacokinetic nonlinear mixed‐effects model analysis. Three bioavailability parameters are considered the population mean bioavailability(F̃), the interindividual variance of bioavailability (ω2F) and the correlation of bioavailability with clearance [cor (CL,F)]. Data are simulated with different degrees of interoccasion variability and/or non‐zero cor(CL,F). With the standard crossover analysis of these data, estimates ofF̃, ωF, and cor(CL,F) are all biased in the presence of interoccasion variability in clearance. Estimates ofF̃and ω2Fobtained from the parallel‐group analysis are not reliable because the approach relies on the assumption that cor(CL,F) is zero. The two correction procedures are very sensitive to random error in the estimates of terminal half‐life. The mixed‐effect model approach produces unbiased estimates of all three bioavailability parameters. These results from simulations are supported by a real data example.Clinical Pharmacology and Therapeutics(1994)55, 623–637; doi:

ISSN:0009-9236    

DOI:10.1038/clpt.1994.79

年代:1994

数据来源: WILEY

摘要:

ObjectiveTo evaluate the pharmacokinetics and pharmacodynamics of recombinant activated factor VII (rFVIIa).MethodsSingle‐dose pharmacokinetics of three dose levels (17.5, 35, and 70 µg/kg) of rFVIIa were investigated in 15 patients with hemophilia with severe factor VIII or factor IX deficiency (with or without inhibitors) while they were in the nonbleeding state and during bleeding episodes. Factor VII clotting activity (FVII:C) was determined 5 minutes before and at 10, 20, and 50 minutes and 2, 4, 6, 8, 12, and 24 hours after rFVIIa administration. Model‐independent pharmacokinetic analysis of FVII:C plasma concentration—time data included determination of plasma clearance, mean residence time, and volume of distribution. rFVIIa recovery was determined from the plasma FVII:C observed 10 minutes after administration. Pharmacodynamic assessments of prothrombin time, activated partial thrombo‐plastic time, and Factor X values obtained concurrently with FVII: C samples were performed.ResultsSufficient data to allow pharmacokinetic parameter calculation were available for 25 nonbleeding episodes in 11 patients (17.5 µg/kg,n= 8; 35 µg/kg,n= 9; 70 µg/kg,n= 8) and for five bleeding episodes in three patients (17.5 µg/kg,n= 2; 35 (µg/kg,n= 2; 35 µg/kg,n= 1). Recovery was calculated during 27 nonbleeding and 17 bleeding episodes. rFVIIa distribution volume is two to three times that of plasma. Median clearance was low—31.0 ml/hr · kg in nonbleeding episodes and 32.5 mg/hr · kg in bleeding episodes. In nonbleeding episodes, median mean residence time was 3.44 hours and median half‐life was 2.89 hours. In bleeding episodes, the elimination rate appears to be higher, with a median mean residence time of 2.97 hours and a median half‐life of 2.30 hours. Recovery was 45.6% during nonbleeding conditions and 43.5% during bleeding episodes (p= 0.0006); it was statistically lower with the highest dose level than with the 17.5 and 35 µ/kg doses (p= 0.007). A significant statistical relationship was observed between values of the prothrombin time and activated partial thromboplastin time, and values of FVII:C with use of maximum effect model.ConclusionsThe pharmacokinetics of rFVIIa are linear in the dose range evaluated. The results suggest potential value of prothrombin time determination in the monitoring of rFVIIa therapy.Clinical Pharmacology and Therapeutics(1994)55, 638–648

ISSN:0009-9236    

DOI:10.1038/clpt.1994.80

年代:1994

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1994)55, 648; doi:10.1038/clpt.1994.81

ISSN:0009-9236    

DOI:10.1038/clpt.1994.81

年代:1994

数据来源: WILEY

摘要:

ObjectiveAdministration of interleukin‐6 partially reproduces the inhibitory effects of the acute‐phase response on cytochrome P450‐dependent drug metabolism. The aim of the study was to determine whether endogenous cytokine has such an effect in patients treated by cyclosporine, which is metabolized by the cytochrome P4503A subfamily.MethodsBlood cyclosporine and serum interleukin‐6 levels were determined in six patients undergoing bone marrow transplantation, as long as they received cyclosporine by continuous infusion. Two serum acute‐phase proteins, C‐reactive protein and α1‐acid glycoprotein, and two cyclosporine metabolites, AM1 and AM9, were also determined.ResultsAt the time of marrow infusion, levels of specific markers of inflammation were low. A peak in interleukin‐6 level was then observed a mean of 10.8 days after transplantation, closely associated with variations in C‐reactive protein levels. A parallel twofold increase in AM1 concentrations was observed, followed by a three‐fold increase in cyclosporine levels, which peaked 4.8 days after interleukin‐6. The times of peak cyclosporine and AM1 levels correlated with the time of peak interleukin‐6 levels. AM9 was detectable in three patients but concentrations fell when interleukin 6 became detectable.ConclusionsAn inflammatory reaction could be an important source of intraindividual variability in cyclosporine pharmacokinetics, possibly through an inhibition of cytochrome P4503A‐dependent enzyme activities by endogenous interleukin‐6. Blood AM1 accumulation might be explained by a secondary metabolic step that is highly sensitive to the inhibitory effect of interleukin‐6.Clinical Pharmacology and Therapeutics(1994)55, 64

ISSN:0009-9236    

DOI:10.1038/clpt.1994.82

年代:1994

数据来源: WILEY

摘要:

ObjectivesThe pharmacokinetic and pharmacodynamic interactions after 7 days of oral treatment with nisoldipine (10 mg twice daily) and propranolol (80 mg twice daily) were investigated in a partially randomized, placebo‐controlled crossover study of 12 healthy volunteers.MethodsAt the end of each treatment period, pharmacokinetic parameters were measured, along with blood pressure, heart rate, cardiac function, systemic hemodynamics, plasma catecholamines, forearm blood flow, and apparent hepatic blood flow (estimated by the clearance of indocyanine green dye).ResultsAfter 7 days of treatment with nisoldipine and propranolol, neither drug altered the other's bioavailability or elimination parameters, and propranolol did not change the area under the plasma concentration—time curve of nisoldipine's metabolite, N‐9425. Nisoldipine alone increased apparent hepatic blood flow and forearm blood flow compared with the other treatment groups but, with the addition of propranolol, both of these parameters were similar to those in the placebo group. Changes in the other hemodynamic parameters were consistent with the known effects of these drugs, and no differences in plasma catecholamine levels were detected.ConclusionsIn contrast to the findings with single‐dose treatment, administration of the combination of nisoldipine and propranolol for 7 days is not associated with any measurable kinetic interactions, although significant hemodynamic interactions do occur.Clinical Pharmacology and Therapeutics(1994)55, 661–669; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1994.83

年代:1994

数据来源: WILEY

摘要:

Cinnarizine was evaluated for the prevention of seasickness in a laboratory and sea study. The effects of 25 mg cinnarizine on the vestibulo‐ocular reflex were investigated in 13 subjects. Significant reduction of the gain in response to sinusoidal oscillations at 0.02, 0.08, and 0.16 Hz (p<0.05) and increased phase lead at 0.16 Hz (p<0.01) were observed. The effect of 25 and 50 mg cinnarizine on seasickness severity was examined in 95 subjects during a voyage in rough seas. Seasickness symptoms were improved in 69% of the subjects by 50 mg cinnarizine versus 35% and 31% in the groups receiving 25 mg cinnarizine and placebo (p<0.05 andp<0.01, respectively). The percentage of vomiting protection provided by 50 mg cinnarizine was 63% (p<0.05). We conclude that 50 mg cinnarizine is an effective drug for the prevention of seasickness. The reduction in vestibular sensitivity observed even after administration of 25 mg cinnarizine may explain the potency of cinnarizine in the prevention of seasickness.Clinical Pharmacology and Therapeutics(1994)55, 670–680; doi:10.1038/clpt.199

ISSN:0009-9236    

DOI:10.1038/clpt.1994.84

年代:1994

数据来源: WILEY

摘要:

This study was undertaken to challenge the hypothesis that short‐term administration of carnitine during exercise can modify skeletal muscle carnitine homeostasis and fuel metabolism in normal humans. With a randomized, blinded, crossover design, subjects received carnitine or placebo at the start of a bicycle ergometer exercise session. During the 2 hours after intravenous administration of 185 µmol/kg carnitine, carnitine kinetics could be described with a central compartment volume of distribution of 200 ml/kg, a total clearance from this compartment of 1.9 ml/min/kg, and a renal clearance of 1.3 ml/min/kg. Carnitine administration had no effect on muscle total carnitine content or the workload‐dependent accumulation of acylcarnitines in skeletal muscle. Carnitine had no effect on the respiratory exchange ratio, muscle lactate accumulation, plasma lactate concentration, muscle glycogen utilization, or plasma β‐hydroxybutyrate concentration during exercise. Thus the skeletal muscle carnitine pool is segregated from dramatic changes in the plasma carnitine pool, and short‐term administration of carnitine has no significant effect on fuel metabolism during exercise in humans.Clinical Pharmacology and Therapeutics(1994)55, 681–692; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1994.85

年代:1994

数据来源: WILEY

摘要:

Central nervous system toxicity of H2‐receptor antagonists has rarely been confirmed by the respective elevated cerebrospinal fluid drug concentrations. We observed two hemodialyzed neurosurgical patients in whom mental deterioration and convulsions developed after intravenous famotidine therapy (10 and 40 mg/day). Their cerebrospinal fluid drug concentrations were grossly elevated (i.e., 160 and 249 ng/ml) compared with those obtained from three other hemodialyzed neurosurgical patients who exhibited no central nervous system reactions (i.e., 47 to 85 ng/ml). In addition, the mean cerebrospinal fluid/plasma drug concentration ratio obtained from these five neurosurgical patients with renal failure (i.e., 0.46) and that from 10 other neurosurgical patients with normal renal function (i.e., 0.41) were about four times greater than that previously reported from non‐neurosurgical patients with normal renal function (i.e., 0.12). Our observation suggests that patients with not only renal dysfunction but also following neurosurgical operations have an excessive accumulation of famotidine in the central nervous system and are more susceptible to the drug‐induced adverse central nervous system reactions.Clinical Pharmacology and Therapeutics(1994)55, 693–700; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1994.86

年代:1994

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1994)55, 701; doi:10.1038/clpt.1994.87

ISSN:0009-9236    

DOI:10.1038/clpt.1994.87

年代:1994

数据来源: WILEY