摘要:

Clinical Pharmacology and Therapeutics(1989)45,459–460; doi:10.1038/clpt.1989.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.58

年代:1989

数据来源: WILEY

摘要:

The pharmacokinetics of theophylline were studied at steady state by stable isotope methodology in nine individual preterm infants. Maturational variables such as postnatal age, postconceptional age, gestational age, duration of treatment, and body weight at the time of the study were analyzed for their influence on theophylline kinetics during the first 6 months of life. The strongest statistical correlations were found between the logarithm of theophylline half‐life (t1/2) and the postnatal age(r= 0.98;p<0.001) and the postconceptional age (r = 0.96;p<0.001). Step‐wise multiple regression analysis revealed postnatal age as the most powerful predictor for theophyllinet1/2in the neonatal period (partial correlation coefficients were 0.78 for postnatal age, 0.19 for postconceptional age, and 0.10 for gestational age). Gestational age, duration of treatment, and weight did not correlate significantly with any pharmacokinetic parameters. We propose that theophylline metabolizing function of the liver increases in a logarithmic fashion during the first 6 months of life.Clinical Pharmacology and Therapeutics(1989)45,461–468; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1989.59

年代:1989

数据来源: WILEY

摘要:

Drug‐induced up‐regulation of β‐adrenergic receptors is impaired in the brains of aged rats but not in myocardia. To investigate age‐related changes in receptor regulation in human beings, young (24 to 35 years of age) and elderly (62 to 78 years of age) healthy volunteers were treated with the β‐adrenergic receptor blocking agent timolol maleate (10 mg b.i.d.) for 8 days. Baseline densities of β2‐adrenergic receptors on polymorphonuclear leukocyte (PMNL) membranes and heart rates were the same in the two age groups. However, systolic blood pressures were higher in the elderly subjects. Administration of timolol produced similar plasma levels in the two groups. In response to timolol, the density of PMNL β‐adrenergic receptors increased at a similar rate and to the same extent (threefold) in both age groups. Likewise, hemodynamic changes were not related to age. These results suggest that up‐regulation of peripheral β2‐adrenergic receptors in human beings is not impaired with aging.Clinical Pharmacology and Therapeutics(1989)45,469–475;

ISSN:0009-9236    

DOI:10.1038/clpt.1989.60

年代:1989

数据来源: WILEY

摘要:

The influence of disulfiram on theophylline metabolism was studied in 20 recovering alcoholics. Ten of the patients, who were selected at random, received 250 mg of disulfiram daily. The other 10 patients received 500 mg of disulfiram daily. Two single‐dose studies of theophylline kinetics were performed— one as a baseline control and the other after 1 week of treatment with disulfiram. With disulfiram pretreatment, the plasma clearance of theophylline was decreased from 105.7 ± 10.2 (mean ± SEM) to 83.1 ± 8.1 ml/kg per hour(p<0.001) in the 250 mg group and from 94.3 ± 13.3 to 65.4 ± 10.7 ml/kg per hour(p<0.001) in the 500 mg group. The elimination half‐life was prolonged significantly in both groups. The percent reduction in theophylline clearance was greater in the 500 mg group (32.5 ± 3.1; range, 21.6 to 49.6) than it was in the 250 mg group (21.2 ± 1.7; range, 14.6 to 29.6;p<0.01). Disulfiram decreased the formation of all theophylline metabolites in smokers in both treatment groups. In each group, the hydroxylation pathway was affected more than the demethylation pathway. These data indicate that at therapeutic doses disulfiram exerts a dose‐dependent inhibitory effect on theophylline metabolism. Depending on the dose of disulfiram, a dose reduction of theophylline by as much as 50% may be necessary to minimize the risk of toxicity.Clinical Pharmacology and Therapeutics(1989)45,476–486; doi:10.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.61

年代:1989

数据来源: WILEY

摘要:

In the mmol/L concentration range, cimetidine and ranitidine suppress superoxide anion generation by isolated intact human neutrophils. However, at normal pharmacologic concentrations in the µmol/L range, even prolonged exposure of neutrophils to these agents has no demonstrable effect on toxic oxygen species synthesis. In vitro inhibition does not involve neutrophil activation‐densensitization or neutrophil cytotoxicity and is reversible to a great extent by drug washout. In the examination of possible free‐radical scavenging action of these drugs, it was demonstrated that both drugs inhibit superoxide anion production by xanthine oxidase but not by chelated iron. This raises the possibility that these agents may bear structural similarities to oxypyrazolopyrimidines such as allopurinol.Clinical Pharmacology and Therapeutics(1989)45,487–494; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.62

年代:1989

数据来源: WILEY

摘要:

Mephenytoin (100 mg) and debrisoquin (10 mg) were administered orally, both separately and together, to 41 healthy subjects. The ratios between the S and R enantiomers of mephenytoin and between debrisoquin and 4‐OH‐debrisoquin in urine were determined by use of GC. These ratios were used as measures of drug hydroxylation. There was no change in the phenotypic trait values of the two drugs when they were coadministered. Mephenytoin and debrisoquin then were coadministered to 253 healthy Swedish subjects, before bedtime, and urine samples were collected at periods of 0 to 8, 8 to 24, and 24 to 32 hours after drug administration. In the first sample, seven of the 253 subjects (2.8%, 95% confidence interval 0.8% to 4.8%) had an S/R ratio of greater than 0.8; this indicated that they were poor hydroxylators ofS‐mephenytoin. In the two consecutive samples, the S/R ratios of mephenytoin did not change in these seven persons, whereas it decreased to less than 0.2 in the third sample in the extensive hydroxylators. As was reported before, there was no relationship between the mephenytoin S/R ratio and the debrisoquin metabolic ratio (rs= 0.01). Coadministration of debrisoquin and mephenytoin before bedtime and urine collection during two consecutive nights allow for an accurate determination of both phenotypes in the population.Clinical Pharmacology and Therapeutics(1989)45,495–499; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1989.63

年代:1989

数据来源: WILEY

摘要:

Probenecid inhibits the elimination of several acidic drugs. In this study, the influence of probenecid on the pharmacokinetics of carprofen was investigated in three healthy volunteers after single peroral administration of 150 mg of RS‐(±)‐carprofen. Carprofen enantiomers and their glucuronides (after cleavage with sodium hydroxide) were measured by use of a stereospecific procedure. The plasma concentrations of S‐(+)‐carprofen were higher than those of R‐(−)‐carprofen at most of the sampling points. Probenecid reduced apparent total and renal clearances for both enantiomers. It also reduced the clearances of the carprofen enantiomers to their glucuronides and the renal clearances of the glucuronides. The differences caused by probenecid were significant, but few stereoselective effects were observed.Clinical Pharmacology and Therapeutics(1989)45,500–505; doi:10.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.64

年代:1989

数据来源: WILEY

摘要:

The disposition parameters and placental transfer of diazepam were determined from blood and both plasma total and free concentration data in five women who had not undergone labor and who received diazepam (5 mg intravenously for 2 minutes) 1½ to 3 hours before cesarean section at term. All patients exhibited smooth log plasma free concentration‐time profiles. In contrast, marked increases in plasma total (approximate 50% increase) and blood (approximate 40% increase) diazepam concentrations occurred at delivery. The plasma total and blood concentration fluctuations were associated with reciprocal variations in diazepam percent free in plasma. For each patient there was a substantial increase in plasma nonesterified fatty acid (NEFA) concentration during the surgical period. There was a significant correlation(p<0.02) between diazepam percent free and plasma NEFA concentration on the day of delivery, suggesting that the fluctuations in percent free, and hence plasma total and blood diazepam concentrations, were mediated in part by variations in plasma NEFA concentration. Disposition parameters were calculated for four of the patients; the mean free plasma clearance of diazepam was 42.5 ml/min/kg, similar to the mean value reported previously for nonpregnant women of comparable age. For each mother‐infant pair at delivery the ratio of total plasma diazepam concentration in umbilical vein plasma to that in maternal vein plasma was considerably greater than unity (mean ± SD = 1.73 ± 0.47), whereas the corresponding ratio for free plasma diazepam concentration was near unity (0.92 ± 0.09). The apparent accumulation of diazepam in the fetal circulation, based on total plasma concentrations, was the result of more extensive plasma binding in umbilical plasma compared with maternal plasma (diazepam percent free of 1.52 ± 0.39 and 2.88 ± 1.05, respectively).Clinical Pharmacology and Therapeutics(1989)45,506–512; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1989.65

年代:1989

数据来源: WILEY

摘要:

To compare the pharmacologic profiles of sublingually and subcutaneously administered buprenorphine, 10 healthy male subjects with histories of opiate abuse were given sublingually administered buprenorphine (1, 2, and 4 mg), subcutaneously administered buprenorphine (1 and 2 mg), and placebo in a double‐blind, double‐dummy, placebo‐controlled study. All active buprenorphine dosages produced a significant degree of miosis but no significant changes in body temperature, blood pressure, or respiratory or heart rate. Buprenorphine produced varying degrees of euphoria related to dose and route of administration but little dysphoria and sedation, as assessed by subscales of the Addiction Research Center Inventory. Subject “liking” for buprenorphine was reported by both observers and subjects. The relative potency of sublingually to subcutaneously administered buprenorphine was calculated for both physiologic and behavioral parameters and found to be approximately two thirds. The results indicated that both sublingual and subcutaneous buprenorphine have a similar profile of effects in opiate abusers.Clinical Pharmacology and Therapeutics(1989)45,513–519; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1989.66

年代:1989

数据来源: WILEY

摘要:

The urinary excretion of meso‐2,3‐dimercaptosuccinic acid (DMSA), which is an effective chelating agent for lead, was determined after the oral administration of 10 mg DMSA/kg to six normal young men. The DMSA that was absorbed was extensively biotransformed. After 14 hours only 2.53% of the administered DMSA was excreted in the urine as unaltered DMSA and 18.1% as altered forms. The unaltered DMSA was 12% of the total DMSA found in the urine. The altered form(s) of DMSA was 88% of the total urinary DMSA. The altered DMSA can be converted to unaltered DMSA by electrolytic reduction, which indicates that the altered forms of DMSA are disulfides. The excretion of altered DMSA reached a peak between 2 and 4 hours after DMSA administration. There were small but statistically significant increases in the excretion of zinc, copper, and lead after DMSA administration. DMSA did not influence the urinary excretion of 27 other metals and elements.Clinical Pharmacology and Therapeutics(1989)45,520–526; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1989.67

年代:1989

数据来源: WILEY