摘要:

Clinical Pharmacology and Therapeutics(1989)46,371–386; doi:10.1038/clpt.1989.1

ISSN:0009-9236    

DOI:10.1038/clpt.1989.154

年代:1989

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1989)46,387–389; doi:10.1038/clpt.1989.1

ISSN:0009-9236    

DOI:10.1038/clpt.1989.155

年代:1989

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1989)46,390–394; doi:10.1038/clpt.1989.1

ISSN:0009-9236    

DOI:10.1038/clpt.1989.156

年代:1989

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1989)46,395–398; doi:10.1038/clpt.1989.1

ISSN:0009-9236    

DOI:10.1038/clpt.1989.157

年代:1989

数据来源: WILEY

摘要:

Theophylline disposition was examined in seven passive smokers, defined as nonsmokers with long‐term exposure to cigarette smoke, and seven age‐matched nonsmokers with minimal smoke exposure. Subjects were given an intravenous infusion of aminophylline (6 mg/kg) and blood samples were drawn before and during the 48‐hour postinfusion period. Clearance for passive smokers was 6.01 × 10−2L/hr · kg and for nonsmokers, clearance was 4.09 × 10−2L/hr · kg (p<0.025). Terminal elimination half‐life for passive smokers was 6.93 hours versus 8.69 hours for nonsmokers (p<0.05). The mean residence time for passive smokers was 9.89 hours. For nonsmokers, the mean residence time was 13.11 hours (p<0.05). These measurements were statistically different, whereas there was no difference in volume of distribution between the groups, suggesting that passive smokers metabolize theophylline more rapidly than nonsmokers. Plasma and urine cotinine and nicotine concentrations were measured in all subjects. There was a significant difference between the subject groups in plasma (p<0.004) and urine (p<0.002) cotinine concentrations. Theophylline clearance correlated with both plasma (r= 0.73,p<0.01) and urine (r= 0.79,p<0.01) cotinine concentrations. Additional studies should be conducted to further define the pharmacokinetic characteristics of passive smokers and to assess the effects of passive smoking on drugs metabolized by the mixed function oxidase system.Clinical Pharmacology and Therapeutics(1989)46,399–407; doi:10.

ISSN:0009-9236    

DOI:10.1038/clpt.1989.158

年代:1989

数据来源: WILEY

摘要:

A potential complicating factor in the characterization of the pharmacokinetics and pharmacodynamics of diltiazem after an oral dose is the presence of two metabolites,N‐demethyldiltiazem and desacetyldiltiazem, in plasma. BothN‐demethyldiltiazem and desacetyldiltiazem have been shown to have pharmacologic activity in animal tissues. It is therefore possible that these metabolites contribute to the pharmacologic effect of diltiazem, but this possibility has not been explored. The purpose of this study was to investigate the pharmacokinetics and pharmacodynamics of diltiazem,N‐demethyldiltiazem, and desacetyldiltiazem. Particular attention was paid to the effect of diltiazem on atrioventricular conduction. Six healthy men received a 120 mg oral dose of diltiazem. Concentrations of diltiazem,N‐demethyldiltiazem, and desacetyldiltiazem in plasma and urine were measured by a sensitive HPLC method. Measures of pharmacologic response (heart rate, blood pressure, and PR interval) were obtained at each blood sampling time. Mean (± SD) peak plasma concentrations of diltiazem,N‐demethyldiltiazem, and desacetyldiltiazem were 174.3 ± 72.7, 42.6 ± 10.0, and 14.9 ± 3.3 ng/ml, respectively. The apparent half‐lives of diltiazem,N‐demethyldiltiazem, and desacetyldiltiazem were 6.5 ± 1.4 hours, 9.4 ± 2.2 hours, and 18 ± 6.2 hours, respectively. BothN‐demethyldiltiazem and diltiazem were eliminated by net renal secretion, whereas the renal clearance of desacetyldiltiazem did not exceed clearance by filtration. BothN‐demethyldiltiazem and desacetyldiltiazem are bound to plasma proteins, with unbound fractions of 0.323 ± 0.035 and 0.230 ± 0.021. These values are similar to the unbound fraction of diltiazem (0.254 ± 0.027). No significant effect of diltiazem on blood pressure or heart rate was noted. However, a prolongation of the PR interval was observed in all six subjects. Furthermore, an apparent clockwise hysteresis in the concentration‐effect relationship was found in four of the six subjects. These findings suggest that some form of acute tolerance to the electrophysiologic effect of diltiazem develops, but the results of pharmacodynamic modeling suggest that this is not caused by the antagonistic effects the metabolites.Clinical Pharmacology and Therapeutics(1989)46,408

ISSN:0009-9236    

DOI:10.1038/clpt.1989.159

年代:1989

数据来源: WILEY

摘要:

The pharmacokinetics of theophylline and its three major metabolites, 3‐methylxanthine, 1‐methylurate, and 1,3‐dimethylurate, were studied during intermittent administration of enoxacin. The addition of enoxacin (400 mg, twice daily) to a theophylline dosing regimen (150 mg, twice daily) resulted in an immediate fall in plasma theophylline metabolite concentrations. Mean steady‐state theophylline concentration in plasma during the dosing interval increased from 3.17 to 8.23 µg/ml. The mean 12‐hour recovery of total theophylline metabolite decreased from 76.3 to 38.6 mg. After the discontinuation of enoxacin, but not theophylline, the plasma theophylline metabolite levels immediately increased to near or above the concentrations observed before enoxacin coadministration. Concurrently, theophylline concentrations decreased to levels equivalent to those observed before enoxacin coadministration. In general, the changes in plasma theophylline concentrations observed after the addition or discontinuation of enoxacin were complete within 3 days.Clinical Pharmacology and Therapeutics(1989)46,420–428; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1989.160

年代:1989

数据来源: WILEY

摘要:

We adapted a technique for isolation of mononuclear leukocyte (MNL) subsets with immunomagnetic beads to the study of β‐adrenergic receptors. Mixed MNL cells were sequentially incubated with monoclonal antibodies specific for certain MNL subsets. Sheep antimouse antibodies coupled to magnetic beads were then added, and the desired MNL subset was pulled out with a magnet. This method yielded subsets with high purity and did not alter β‐receptor density or function. Healthy volunteers were treated for 7 days with the β2‐selective agonist terbutaline (5 mg t.i.d.). Terbutaline treatment decreased β‐receptor number and isoproterenol‐stimulated cyclic adenosine monophosphate (cAMP) generation in natural killer cells, helper T cells, and suppressor/cytotoxic T cells but not in B cells. The decrease was greatest in suppressor/cytotoxic T cells and least in helper T cells. Thus β‐adrenergic receptor regulation by agonists appears to differ among MNL subsets.Clinical Pharmacology and Therapeutics(1989)46,429–439; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1989.161

年代:1989

数据来源: WILEY

摘要:

The effect of high‐dose ibuprofen, a nonsteroidal anti‐inflammatory drug (NSAID), on the blood pressure of treated hypertensive patients was evaluated in a randomized, placebo‐controlled, double‐blind, crossover trial with 24‐hour ambulatory blood pressure monitoring. Twelve middle‐aged black women with essential hypertension, controlled with 50 mg hydrochlorothiazide per day, randomly received 3200 mg ibuprofen and a placebo for 8 days. Each treatment phase was separated by a 1‐week washout period. Ambulatory blood pressure monitoring (ABPM), body weight, and 24‐hour urinary excretion of sodium, creatinine, and prostaglandin E2(PGE2) were determined at the end of each treatment phase. Mean (± SEM) 24‐hour systolic and diastolic blood pressures were 122/85 (±2.9/1.7) and 125/85 (±3.0/1.1) during the placebo and ibuprofen phases, respectively. Mean ABPM during six consecutive 4‐hour periods also revealed no significant differences between placebo and ibuprofen. We conclude that 3200 mg ibuprofen per day for up to 1 week induces little change in blood pressure in hypertensive patients who are receiving hydrochlorothiazide.Clinical Pharmacology and Therapeutics(1989)46,440–444;

ISSN:0009-9236    

DOI:10.1038/clpt.1989.162

年代:1989

数据来源: WILEY

摘要:

Dilevalol, an agent that combines nonselective β‐blocking and β2‐mediated vasodilating properties, was compared with placebo in 16 subjects with moderate hypertension in a double‐blind crossover study. Dilevalol or a placebo was administered intravenously in bolus injections of 25, 50, and 50 mg at 15‐minute intervals. Fifteen minutes after a cumulative dose of 125 mg, the blood pressure was lowered by 11/9 mm Hg, compared with 2/1 mm Hg after placebo (p<0.01 between groups for systolic and diastolic blood pressure), an effect that persisted for at least 105 minutes. Standing systolic blood pressure was also lowered in dilevalol‐treated patients without orthostatic symptoms. No significant effects on heart rate were noted. Fifteen minutes after the last dose of dilevalol, plasma norepinephrine levels increased from a baseline of 200 ± 24 to 495 ± 44 pg/ml (p<0.01), compared with a nonsignificant rise from 262 ± 21 to 306 ± 28 pg/ml with placebo vehicle. Dilevalol also increased α‐human atrial natriuretic factor by 5.4 pg/ml, compared with 0.5 pg/ml after placebo (p<0.01 between groups). Plasma renin activity and plasma epinephrine, aldosterone, and cyclic guanosine monophosphate levels were unchanged by dilevalol. There were no significant adverse effects with dilevalol administration. Compared with placebo, dilevalol given intravenously appears to be safe and effective antihypertensive treatment.Clinical Pharmacology and Therapeutics(1989)46,445–450; doi:

ISSN:0009-9236    

DOI:10.1038/clpt.1989.163

年代:1989

数据来源: WILEY