摘要:

NONMEM, a computer program that uses the method of extended least‐squares analysis, has been advocated as a means of obtaining estimates of population pharmacokinetic parameters when only fragmentary information can be obtained from subjects. To assess the performance of this program, we compared NONMEM with traditional methods for the estimation of population pharmacokinetic parameters with data collected during a phase III clinical trial of alprazolam. NONMEM estimates of the population mean clearance and its coefficient of variation were identical to the estimates obtained with traditional pharmacokinetic techniques. Moreover, NONMEM estimates of these parameters remained stable even when as few as three data points were available per subject. NONMEM estimates of the mean volume of distribution and its coefficient of variation appear to be overestimated, apparently because of the sampling scheme used to generate data for the NONMEM analysis. Suggestions for the effective use of NONMEM in clinical trials, to maximize the benefits of this approach, are provided. Our results lend further support for the use of NONMEM to estimate population pharmacokinetic parameters of a drug from data generated during phase III clinical trials.Clinical Pharmacology and Therapeutics(1986)39,605–612; doi:10.1038/clpt.1986

ISSN:0009-9236    

DOI:10.1038/clpt.1986.107

年代:1986

数据来源: WILEY

摘要:

Pharmacokinetic parameters of (±)‐, (+)‐, and (−)‐gossypol were determined in humans and dogs after a single oral or intravenous dose. Mean (±SD) oral bioavailability of (±)‐gossypol in dogs was 30.9% ± 16.2%. Studies in dogs who received single intravenous injections revealed that the elimination t½and volume of distribution of (+)‐gossypol were five and six times those of (−)‐gossypol, respectively, whereas total body clearance and the AUC of the two enantiomers were similar. Data from men receiving the compounds orally show that the average peak plasma concentration and the AUC of (+)‐gossypol are significantly greater than those of the (−)‐isomer. The rate constants of α, β, ka, k21, and k10for (−)‐gossypol are significantly greater than those for (+)‐gossypol, indicating higher rates of mass transfer of the (−)‐species. In humans the elimination t½of (+)‐gossypol was 29 times as that of (−)‐gossypol, a difference that is more striking than that found in dogs. The elimination t½of (±)‐gossypol in humans averages 286 ± 179 hours.Clinical Pharmacology and Ther

ISSN:0009-9236    

DOI:10.1038/clpt.1986.108

年代:1986

数据来源: WILEY

摘要:

Alizapride is a new substituted benzamide with suggested superior antiemetic efficacy to and fewer side effects than metoclopramide. High‐dose alizapride (4 mg/kg x five doses) was compared with high‐dose metoclopramide (2 mg/kg x five doses) in a prospective, randomized, double‐blind trial in 62 évaluable patients undergoing strongly emetic cancer chemotherapy. Patients receiving metoclopramide experienced significantly fewer vomiting episodes than patients receiving alizapride (median of three episodes vs. eight episodes; P<0.001). Metoclopramide was more effective in decreasing the volume of emesis than was alizapride (median of 100 ml vs. 360 ml; P<0.02). Seventy‐two percent of the patients receiving alizapride and 57% of those receiving metoclopramide experienced side effects. High‐dose metoclopramide is an effective antiemetic in patients receiving cancer chemotherapy. Alizapride is less effective and has more side effects than metoclopramide. We do not recommend the further use of alizapride.Clinical Pharmacology and Therapeutics(1986)39,619–624; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1986.109

年代:1986

数据来源: WILEY

摘要:

Our study was conducted to assess the effects of multiple doses of nicotine chewing gum on a variety of measures of cigarette smoking, affect, and physiologic response. Cigarette smokers resided on a research unit for the duration of the study, during which time their smoking behavior was measured during nine 12‐hour test sessions. At the start of each session and every 2 hours thereafter, subjects received oral doses of nicotine (2 or 4 mg) or placebo in the form of a chewing gum (nicotine polacrilex). Each dose of active drug and placebo was given for three sessions in a randomized block sequence. Total number of puffs per day was significantly decreased at both the 2 and 4 mg doses when compared with placebo, and the total number of cigarettes smoked per day was significantly decreased at the 4 mg dose. There were dose‐related changes in certain subjective effects: Self‐reported ratings of dose strength were directly related to dose, desire to smoke tended to be inversely related to dose, and prominent measures of abuse liability did not change. The only cardiovascular measure that was significantly changed by nicotine dose was systolic blood pressure, which showed an attenuation of the diurnal pattern as the dose increased.Clinical Pharmacology and Therapeutics(1986)39,625–630; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1986.110

年代:1986

数据来源: WILEY

摘要:

Patients with burns clinically appear to require considerably larger doses of vancomycin than normal to attain therapeutic serum concentrations. It has been presumed that this phenomenon is a result of increased renal elimination of this drug consequent to increased glomerular filtration rates in such patients, as has been documented with aminoglycoside antibiotics. We measured the serum clearance of vancomycin in 10 patients with burns and found this parameter to correlate closely with creatinine clearance (serum clearance = 12.5 + 0.695 creatinine clearance; r = 0.932; P<0.001). The slope of this relationship was similar to that reported by other investigators in patients not suffering from thermal injury. We conclude that at all levels of renal function, patients with burns clear vancomycin in a manner similar to that of other patients. Consequently, renal function can be used to select a dosing regimen for vancomycin in such patients.Clinical Pharmacology and Therapeutics(1986)39,631–634; doi:10.1038/clpt.1986.1

ISSN:0009-9236    

DOI:10.1038/clpt.1986.111

年代:1986

数据来源: WILEY

摘要:

Six patients with chronic renal failure (CRF group) and four healthy subjects (HS group) were given 5 mg oral and intravenous doses of bumetanide in a random, crossover design. The CRF group had significantly lower plasma and renal clearances, resulting in a five‐ to sixfold reduction in the fractional urinary excretion of the drug. The percent free drug in plasma for the CRF group was more than double that for the HS group, and significant correlations were observed for volume of distribution at steady state vs. percent free (r = 0.661; P<0.05), nonrenal clearance vs. percent free (r = 0.796; P<0.01), and renal clearance vs. creatinine clearance (r = 0.995; P<0.001). Although bioavailability was relatively consistent among the HS (0.664 ± 0.112) and CRF (0.689 ± 0.149) groups, the absorption‐time profiles were more irregular for both groups. Cumulative sodium excretion and overall efficiency of response to bumetanide did not differ significantly between the two routes of administration in either group.Clinical Pharmacology and Therapeutics(1986)39,635–645; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1986.112

年代:1986

数据来源: WILEY

摘要:

The simultaneous dosing of two drugs with co‐regulated genetic polymorphisms determined by a single cytochrome P‐450 isozyme could result in competitive inhibition of metabolism. We investigated this hypothesis in vivo by studying the interaction of mephobarbital and mephenytoin in eight normal subjects with wide variability inS‐mephenytoin 4‐hydroxylation. Each received oral racemic mephenytoin (100 mg) alone and, on a separate occasion, 1 hour after oral racemic mephobarbital (200 mg). After mephenytoin dosing alone, the 8‐hour urinary enantiomeric(R/S)ratio indicated one poor (PM), one intermediate (IM), and six extensive (EM) metabolizers. Total intrinsic clearance ofS‐mephenytoin varied more than 100‐fold, whereas the range forR‐mephenytoin was only twofold. The urinaryR/Sratio correlated (r = 0.92) with the enantiomeric ratio of the plasma AUCs over the same period, indicating no stereoselectivity in renal clearance. When mephenytoin was taken in the presence of mephobarbital, peak levels and AUC ofS‐mephenytoin increased while those of theR‐enantiomer remained unchanged. Accordingly, theR/Sratios in both plasma and urine were reduced, with the change rank order—related to the control value of the total intrinsic clearance ofS‐mephenytoin, (i.e., greatest in the most extensive EM). Thus the urinaryR/Sratio can be used as a measure of the enantiomeric ratio of the plasma concentrations over the same time period of collection. Moreover, this ratio may be used to detect drug interactions that involve the cytochrome P‐450 isozyme(s) responsible for the polymorphic 4‐hydroxylation of mephenytoin. Such an interaction approach may be applied to the identification of other drugs whose metabolism may be determined in the same genetic fashion as that ofS‐mephenytoin.Clinical Pharmacology and Therapeutics(1986)39,646

ISSN:0009-9236    

DOI:10.1038/clpt.1986.113

年代:1986

数据来源: WILEY

摘要:

The disposition of methylprednisolone was examined in six normal subjects after the injection of 20 mg iv methylprednisolone sodium succinate. Disposition studies were performed both without and with ketoconazole, 200 mg/day, for 6 days. Ketoconazole increased the methylprednisolone AUC and mean residence time (by 135% and 66%, respectively) and decreased clearance (60%), the terminal phase slope, and the volume of distribution. These findings are typical of macrolide antibiotic alteration of methylprednisolone disposition and consistent with reports of inhibition of drug metabolism by ketoconazole. Methylprednisolone reduced the 24‐hour cortisol AUC by 44%, but morning cortisol concentrations returned to normal. Ketoconazole with methylprednisolone further reduced the 24‐hour cortisol AUC and suppressed morning cortisol concentrations. Thus ketoconazole inhibits methylprednisolone disposition and extends the adrenal suppression effects of this corticosteroid.Clinical Pharmacology and Therapeutics(1986)39,654–659; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1986.114

年代:1986

数据来源: WILEY

摘要:

There is a debate whether the fall in plasma cortisol concentrations after the early morning dosing of clonidine represents drug effect or normal diurnal variation. We compared the cortisol patterns of children after a 7:30 AM oral dose of clonidine (0.075 or 0.150 mg/m2) with the cortisol concentrations that resulted from diurnal variation. Some subjects had the diurnal study on day 1 and the clonidine study on day 2, whereas for others the testing sequence was reversed. Our results indicate that clonidine, in either dose, does not cause a fall in plasma cortisol levels greater than that with normal diurnal variation.Clinical Pharmacology and Therapeutics(1986)39,660–663; doi:10.1038/clpt.1986.1

ISSN:0009-9236    

DOI:10.1038/clpt.1986.115

年代:1986

数据来源: WILEY

摘要:

We studied blood pressure (BP) and heart rate (HR) responses in 12 patients with hypertension who were receiving cetamolol, a cardioselective β‐blocker with intrinsic sympathomimetic activity. The BP and HR parameters were evaluated at rest (casual, office readings), with ambulatory BP monitoring, and after treadmill exercise testing. At a mean (± SD) dose of 46 ± 21 mg/day, casual supine BP decreased by 10/12 mm Hg (P<0.05 for systolic; P<0.01 for diastolic) compared with placebo, while HR decreased 4 bpm. Cetamolol resulted in a significant reduction in the mean 24‐hour systolic BP. The most striking reduction occurred in the BP at work (23 mm Hg), with almost no decrease in the BP during sleep. Ambulatory HR reductions occurred while the subjects were at work (9 bpm; P<0.05) but not while at home (awake) or during sleep. The mean duration of exercise was the same during cetamolol and placebo phases, but both HR and BP fell significantly at peak performance after cetamolol. These data suggest that cetamolol reduces BP without lowering HR at rest. During periods of increased adrenergic activity such as work and dynamic exercise, both HR and BP are reduced.Clinical Pharmacology and Therapeutics(1986)39,664–668; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1986.116

年代:1986

数据来源: WILEY