摘要:

Clinical Pharmacology and Therapeutics(1991)49, 1–5; doi:10.1038/clpt.1991

ISSN:0009-9236    

DOI:10.1038/clpt.1991.1

年代:1991

数据来源: WILEY

摘要:

Sixteen patients treated with oral isoniazid, pyrazinamide, rifampin, and intramuscular streptomycin for tuberculous meningitis were studied. The concentrations of isoniazid, pyrazinamide, rifampin, and streptomycin in cerebrospinal fluid (CSF) obtained 3 hours after administration were 2.40, 34.78, 0.29, and 3.78 μg/ml, respectively. The CSF concentrations of isoniazid and pyrazinamide were well above the minimum inhibitory concentration forMycobacterium tuberculosis. Concentrations of rifampin and streptomycin were above the minimal inhibitory concentration initially but declined below the minimal inhibitory concentration at later times. The CSF penetration of isoniazid, pyrazinamide, rifampin, and streptomycin was about 89%, 91%, 5%, and 20%, respectively. In eight patients who received antituberculous drugs in combination with steroids, the mean CSF and serum concentrations, as well as CSF/serum ratios at various intervals of treatment, were not statistically different(p>0.05) from those of the eight patients who did not receive steroids.Clinical Pharmacology and Therapeutics(1991)49, 6–12; doi:10.1038/clpt.199

ISSN:0009-9236    

DOI:10.1038/clpt.1991.2

年代:1991

数据来源: WILEY

摘要:

Delayed hypersensitivity reactions are among the most severe adverse effects of the sulfonamides in current clinical use. These reactions appear to occur because of differences in the metabolism and detoxification of reactive metabolites of the sulfonamides.N‐Acetylation is a major metabolic pathway for the sulfonamides. Slow acetylation phenotype might be a risk factor for the development of these reactions. We determined the acetylation phenotype of 21 patients who had suffered hypersensitivity reactions to the sulfonamides. There were 11 females and 10 males in the group, with a mean age of 15 years (age range, 1.8 to 50 years). Their acetylator phenotype was determined by determining the ratio of urinary caffeine metabolites (1‐methylxanthine to 5‐amino‐6‐formylmethyluracil after an oral dose of 50 mg caffeine). Nineteen (90%) of the patients were slow acetylators compared to a 55% incidence of slow acetylators in a race‐matched control population(p<0.008). This suggests that a slow acetylator phenotype is a risk factor for the development of sulfonamide hypersensitivity reactions and provides further support for the role of imbalances in genetically determined pathways of metabolism and detoxification of the sulfonamides in the pathogenesis of these reactions.Clinical Pharmacology and Therapeutics(1991)49, 13–17; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1991.3

年代:1991

数据来源: WILEY

摘要:

The metabolism of imipramine in six poor metabolizers of mephenytoin was compared with the metabolism of 16 extensive metabolizers of mephenytoin from an earlier study. Each subject was given single doses of 100 mg imipramine hydrochloride and 100 mg desipramine hydrochloride on separate occasions. Imipramine demethylation clearance was 0.74 L · min−1(mean; range, 0.31–1.24) in poor metabolizers of mephenytoin compared with 1.43 L · min−1(mean; range, 0.61–3.81) in extensive metabolizers of mephenytoin(p= 0.01, Mann‐WhitneyUtest). It has previously been shown that the imipramine clearance by way of other pathways and desipramine oral clearance, both largely representing 2‐hydroxylation, are considerably lower in poor metabolizers of sparteine than in extensive metabolizers of sparteine. In contrast, five subjects who were poor metabolizers of mephenytoin and extensive metabolizers of sparteine and a control group of 11 subjects who were extensive metabolizers of mephenytoin and sparteine showed no statistically significant difference with regard to these parameters. One subject who was a poor metabolizer of mephenytoin and sparteine had the lowest imipramine oral clearance of all 22 subjects studied. In conclusion, this and an earlier study show that the oxidation of imipramine is mediated by means of two different polymorphic P450 isozymes, 2‐hydroxylation by way of the sparteine oxygenase (P450IID6) and demethylation by way of the mephenytoin oxygenase (P450IIC8).Clinical Pharmacology and Therapeutics(1991)49, 18–23; doi:1

ISSN:0009-9236    

DOI:10.1038/clpt.1991.4

年代:1991

数据来源: WILEY

摘要:

The dose‐response curves of betaxolol and atenolol were compared in 140 patients with mild to moderate essential hypertension. Patients with a supine diastolic blood pressure of 95 to 115 mm Hg at the end of a 4‐week single‐blind placebo washout phase were randomized (double‐blind) to receive either betaxolol or atenolol in a dose‐escalation manner. The dose (5 mg, 10 mg, and 20 mg betaxolol; 25 mg, 50 mg, and 100 mg atenolol) was increased if the supine diastolic blood pressure remained greater than 90 mm Hg after 4 weeks at each level. The final dose in the escalation phase was continued for an additional 12 weeks and then followed by a 2‐week placebo phase. The data were analyzed with a population model using the program NONMEM (nonlinear mixed effects model). Atenolol exhibited a graded dose‐response curve, whereas the lowest dose of betaxolol produced maximum or near‐maximum effect. The estimated maximum effect (drug plus possibly unmeasured placebo effect) was similar for both treatments, about 13 mm Hg (95% confidence interval, 10 to 15 mm Hg). A trend toward less inter‐individual variability (coefficient of variation) was apparent for betaxolol compared to atenolol, 19% (95% confidence interval, 0% to 29%) versus 31% (95% confidence interval, 0% to 47%). The intra‐individual variability (standard deviation) in supine diastolic blood pressure, 5.9 mm Hg (95% confidence interval, 5.2 to 6.5 mm Hg), did not differ significantly between drugs despite significantly greater intraindividual variability (coefficient of variation) in atenolol concentrations, 62% (95% confidence interval, 48% to 73%) versus 26% (95% confidence interval, 22% to 29%) for betaxolol.Clinical Pharmacology and Therapeutics(1991)49, 24–31; d

ISSN:0009-9236    

DOI:10.1038/clpt.1991.5

年代:1991

数据来源: WILEY

摘要:

The influence of cimetidine on the absorption and disposition of moclobemide was examined in eight healthy male subjects. A single 100 mg intravenous and 100 mg oral dose of moclobemide was administered before and after 2 weeks of cimetidine administration (200 mg five times a day). The data on intravenous administration indicated that cimetidine produced a statistically significant alteration in the following disposition parameters (mean values for control versus cimetidine): systemic clearance, 46.6 versus 28.3 L/hr; mean residence time, 2.1 versus 3.2 hours; elimination half‐life, 1.6 versus 2.3 hours. There was no significant difference in the steady‐state volume of distribution. The absolute oral bioavailability of moclobemide increased significantly after cimetidine administration (54% versus 68%), as did the maximum plasma concentration after a single oral dose (575 versus 787 ng/ml). There were no differences in the mean absorption time or time to achieve maximum concentration. The values of systemic and apparent oral clearances of moclobemide after cimetidine administration were directly related to the corresponding control values before cimetidine. In contrast, the percentage change in clearance was essentially independent of the corresponding initial control clearance value.Clinical Pharmacology and Therapeutics(1991)49, 32–38; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1991.6

年代:1991

数据来源: WILEY

摘要:

The effects of magnesium hydroxide on the pharmacokinetics and pharmacodynamics of glipizide were studied in eight healthy volunteers in a randomized crossover trial. After an overnight fast, 5 mg glipizide was given with either 150 ml water or water containing 850 mg magnesium hydroxide. Magnesium hydroxide increased the areas under the plasma glipizide concentration‐time curves (AUC) from 0 to ½ hour and from 0 to 1 hour by 180%(p<0.05) and 69%(p<0.05), respectively. The peak plasma concentration, time to peak, total AUC, elimination half‐life, and mean residence time of glipizide remained unchanged. The incremental plasma insulin area from 0 to ½ hour increased by 85%(p<0.05), and the time to maximal insulin response was reduced(p<0.05) during the magnesium hydroxide phase. The corresponding decremental plasma glucose area increased fourfold(p<0.05), and the maximal glucose decrease was 35% greater(p<0.05) than during the control phase. We conclude that the concomitant ingestion of magnesium hydroxide and glipizide may result in accelerated absorption of glipizide and increased early insulin and glucose responses.Clinical Pharmacology and Therapeutics(1991)49, 39–43; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1991.7

年代:1991

数据来源: WILEY

摘要:

It has been realized recently that the primary metabolism of caffeine in humans is catalyzed by P‐450IA2 and that the rate of caffeine metabolism can be estimated from a metabolic ratio in a single urine sample. A population of 178 students including 19 smokers were subjected to this caffeine test to establish their P‐450IA2 index. Both stated numbers of cigarettes smoked per day and urinary cotinine levels as a confirmatory measure correlated significantly with enzyme activity showing dose‐effect relationships (r = 0.62 and 0.89, respectively). Nevertheless, more nonsmokers than smokers had the highest enzyme indexes, suggesting that dietary elements or other factors may determine P‐450IA2 activities in populations. Because P‐450IA2 is a monooxygenase that may be confined to the liver, caffeine reveals directly the Ah‐receptor‐dependent enzyme induction only in the liver, but it may also be a signal of induction elsewhere.Clinical Pharmacology and Therapeutics(1991)49, 44–48; doi:10.

ISSN:0009-9236    

DOI:10.1038/clpt.1991.8

年代:1991

数据来源: WILEY

摘要:

Responsiveness of superficial hand veins to local infusions of noradrenaline was compared in patients with primary varicose veins and in healthy volunteers by use of the dorsal hand vein technique. Patients with varicose veins required significantly higher doses of noradrenaline for half‐maximal venoconstriction than the dose required by control subjects (geometric mean, 11.6 ng/min in patients compared with 4.8 ng/min in control subjects;p= 0.006). Noradrenaline responsiveness in varicose veins was not significantly different from hand vein responsiveness in the same patients. Our findings indicate a constitutional decrease in venous a‐adrenergic receptor responsiveness in patients with varicosities. Dilation of varicose veins does not further affect noradrenaline‐induced venoconstriction.Clinical Pharmacology and Therapeutics(1991)49, 49–52; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1991.9

年代:1991

数据来源: WILEY

摘要:

The concentration‐effect relationship of 0.25 mg intravenous timolol with and without pretreatment with 100 mg quinidine was studied in six healthy young volunteers with a randomized, double‐blind, crossover study design. Blockade of cardiac β‐adrenoceptors was assessed by determining the dose ratios (DR) of isoproterenol infusions required to increase heart rate by 25 beats/min before and after timolol infusion. The logarithm of timolol concentration in plasma was linearly related to the logarithm (DR–1) of isoproterenol infusion, with a mean Pearson correlation coefficient of 0.89 ± 0.11 (± SD;n= 24) at timolol concentrations well below 1 ng/ml. The increases in cyclic adenosine monophosphate (cAMP) and norepinephrine plasma levels caused by isoproterenol infusions were attenuated after timolol. Quinidine administration increased timolol plasma levels and cardiac β‐blocking effects by 10% to 40%. It was concluded that timolol at concentrations below 1 ng/ml in plasma competitively antagonizes cardiac and noncardiac effects of isoproterenol infusions. Timolol effects are augmented after quinidine administration. The β‐blockade occurring at low plasma levels can explain side effects and actions of ocularly applied timolol.Clinical Pharmacology and Therapeutics(1991)49, 53–58; doi:1

ISSN:0009-9236    

DOI:10.1038/clpt.1991.10

年代:1991

数据来源: WILEY