摘要:

Clinical Pharmacology and Therapeutics(1989)45,217–219; doi:10.1038/clpt.1989.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.20

年代:1989

数据来源: WILEY

摘要:

This study examined the effect of ferrous sulfate, a widely used iron treatment, on levodopa bioavailability in normal subjects. A 250 mg tablet of levodopa was taken with and without a 325 mg tablet of ferrous sulfate by eight normal subjects in a randomized crossover trial. When levodopa was taken with ferrous sulfate there was a 55% decrease in peak levodopa levels (3.6 ± 2.6 vs 1.6 ± 0.82 nmol/ml;p<0.05) and a 51% decrease in AUC (257 ± 133 vs 125 ± 51 nmol · min/ml;p<0.01). Persons with the highest peak levodopa levels and AUC after levodopa alone had the greatest reduction in peak levodopa levels and AUC after levodopa ingestion with ferrous sulfate. Iron in its ferrous state is oxidized rapidly to the ferric state in the presence of levodopa at pHs found in the small intestine. In the ferric state, iron binds very strongly to levodopa. Chelation of iron by levodopa is the likely mechanism for this drug interaction. The clinical significance of this interaction is yet to be established.Clinical Pharmacology and Therapeutics(1989)45,220–225; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.21

年代:1989

数据来源: WILEY

摘要:

We sought to use a previously derived pharmacodynamic model for 72‐hour etoposide infusions to adaptively control administration of this agent and to demonstrate that more predictable toxicity could be obtained with this dosing scheme. A randomized crossover study design was used to compare “standard” dosing (125 mg/m2/day) to adaptive control, with dose adjustment at 28 hours based on the 24‐hour plasma level. A total of 31 patients received 86 cycles of chemotherapy, 36 by standard dosing and 50 by adaptive control. However, there was no demonstrable advantage to the adaptive control scheme, because of apparent bias of the previous model. A new model was proposed that also included serum albumin, performance status, and prior RBC transfusions as measures of interpatient pharmacodynamic variability. We conclude that adaptive control dosing of etoposide is feasible but that the therapy must be individualized for both pharmacokinetic and pharmacodynamic variability.Clinical Pharmacology and Therapeutics(1989)45,226–233; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1989.22

年代:1989

数据来源: WILEY

摘要:

Six healthy volunteers received a single caffeine dose after pretreatment with norfloxacin, pipemidic acid, or placebo in a crossover, randomized, single‐blind clinical trial. Quinolones altered the pharmacokinetics of caffeine, with a significant increase in the AUCs and a decrease in plasma clearance. The elimination half‐life increased significantly with pipemidic acid. The apparent volume of distribution, mean renal clearance, and time to reach maximum caffeine concentrations remained unaltered. There was a decline in caffeine metabolite levels in the 24‐hour urine samples for both quinolone treatments, suggesting that pipemidic acid and, to a lesser degree, norfloxacin inhibit metabolism of theN‐demethylation pathways of caffeine. The practical consequence of this observation could be caffeine accumulation during repeated intake of coffee. In two additional healthy volunteers under a controlled multiple‐dose regimen of caffeine ingestion, administration of pipemidic acid for 2 days caused a fourfold increase in the plasma concentrations of caffeine.Clinical Pharmacology and Therapeutics(1989)45,234–240; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1989.23

年代:1989

数据来源: WILEY

摘要:

Orthostatic hypotension, one of tricyclic antidepressant treatment's side effects, is also a factor in limiting adequate antidepressant dosing. We tested in a double‐blind, crossover, placebo‐controlled study the effect of low doses (4 mg/t.i.d.) of yohimbine in 12 patients with depression with ciomipramine‐induced orthostatic hypotension. Yohimbine, a selective α2‐adrenoceptor antagonist, had a favorable effect in orthostatic hypotension and induced a significant increase in blood pressure. A pharmacodynamic and pharmacokinetic interaction between yohimbine and clomipramine or demethylclomipramine was discussed.Clinical Pharmacology and Therapeutics(1989)45,241–251; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1989.24

年代:1989

数据来源: WILEY

摘要:

The intersubject variability in blood pressure response to 0.44 mg/kg intravenous phenylpropanolamine (d,l‐norephedrine) was studied in 10 normal subjects. A phenylpropanolamine or placebo infusion was administered over 45 minutes on separate days according to a double‐blind, balanced protocol. Blood pressure increased by 24 ± 13/16 ± 7 mm Hg (systolic/diastolic, mean ± SD) after the phenylpropanolamine infusion and was statistically different from the placebo infusion response (7 ± 5/8 ± 3 mm Hg). Phenylpropanolamine infusions were terminated early in two subjects (hyper‐responders) after 0.31 and 0.23 mg/kg because of excessive increases in blood pressure (52/30 and 34/21 mm Hg, respectively). The hyperresponders had the lowest peak serum phenylpropanolamine concentrations. These data suggest that considerable intersubject variability exists in the blood pressure response to intravenous phenylpropanolamine. A pharmacokinetic basis for the variability in response to racemic phenylpropanolamine was not observed. A relationship did not exist within the group between blood pressure effect and serum concentration but did exist within each subject. Therefore phenylpropanolamine's blood pressure effect in an individual cannot be predicted solely from a serum concentration of racemic drug.Clinical Pharmacology and Therapeutics(1989)45,252–259; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1989.25

年代:1989

数据来源: WILEY

摘要:

The two monoamine oxidase (MAO) inhibitors phenelzine and brofaromine given for 2 to 3 weeks were compared in six volunteers. Blood pressure sensitivity to intravenous tyramine increased 2.6‐fold during phenelzine (60 mg/day) and 4.8‐fold during brofaromine, whereas sensitivity to oral tyramine increased more during phenelzine (15.7‐fold vs 8.5‐fold). After withdrawal of phenelzine, pressor sensitivity to oral tyramine returned to control values within 2 and for more than 8 weeks. Relative bioavailability of conjugated tyramine was elevated sixfold by brofaromine and 11.6‐fold by phenelzine. Urinary elimination of tryptamine increased during phenelzine and brofaromine to 12.7‐fold and threefold, respectively. 3‐Methoxy‐4‐hydroxyphenylglycol (MHPG) and 3‐methoxy‐4‐hydroxymandelic acid (VMA) excretion decreased during brofaromine significantly by 72% and 49%, respectively. The nonsignificant decrease of MHPG excretion and the increase of intravenous tyramine pressor sensitivity caused by phenelzine are significantly related. The data suggest that the selective reversible MAO‐A inhibitor brofaromine has a larger therapeutic safety than phenelzine.Clinical Pharmacology and Therapeutics(1989)45,260–2

ISSN:0009-9236    

DOI:10.1038/clpt.1989.26

年代:1989

数据来源: WILEY

摘要:

The safety, tolerability, and pharmacologic activity of WEB 2086, a novel, specific platelet activating factor antagonist, were examined in two double‐blind, placebo‐controlled, within‐subject crossover studies. In each study, WEB 2086 (three times 40 mg/day or three times 100 mg/day) was administered for 7 days to 12 healthy volunteers. Pharmacologic activity of the compound was monitored with ex vivo platelet activating factor–induced platelet aggregation. Multiple administration of WEB 2086 resulted in a continuous, almost complete inhibition of this aggregation. Nevertheless, no clinically significant drug‐related effects on vital and laboratory parameters or obvious drug‐dependent adverse reactions were observed. In conclusion, the performed studies confirmed earlier findings that WEB 2086 was an effective platelet activating factor antagonist in human beings and, furthermore, showed no side effects that would provide objections against further clinical trials with this substance in patients.Clinical Pharmacology and Therapeutics(1989)45,270–276; doi:10.103

ISSN:0009-9236    

DOI:10.1038/clpt.1989.27

年代:1989

数据来源: WILEY

摘要:

Ten normal subjects of known debrisoquin phenotype (six extensive (EM) and four poor (PM) metabolizers) were given of 5 mg glyburide (glibenclamide) suspension orally. Plasma glyburide and urinarycis‐3‐hydroxy‐(30H) and trans‐4‐hydroxyglyburide (40H) were measured by a sensitive HPLC assay. No unchanged glyburide was detected in urine but both metabolites were identified in urine in all subjects. There were no significant differences in any respect with regard to glyburide metabolism or pharmacokinetics between EM and PM of debrisoquin. Estimated mean elimination half‐life of glyburide was 3.3 ± 1.1 hours for EM and 2.5 ± 0.4 hours for PM. In one subject (EM), with reduced excretion of 30H, glyburide was detected in plasma at 24 and 30 hours and the apparent elimination half‐life was 9.3 hours. There was no significant difference for total metabolite recovery between EM and PM. Eight of the subjects (six EM and two PM) had previously taken part in a study of tolbutamide metabolism, and a comparison of metabolic clearances by hydroxylation for the two sulfonylureal drugs showed no significant correlation. Glyburide is therefore unlikely to be metabolized by the enzymes that metabolize either debrisoquin or tolbutamide.Clinical Pharmacology and Therapeutics(1989)45,277–284; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1989.28

年代:1989

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1989)45,284–284; doi:10.1038/clpt.1989.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.29

年代:1989

数据来源: WILEY