摘要:

Clinical Pharmacology and Therapeutics(1990)48,1–9; doi:10.1038/clpt.1990.1

ISSN:0009-9236    

DOI:10.1038/clpt.1990.110

年代:1990

数据来源: WILEY

摘要:

Interracial differences in drug responsiveness can be accounted for, at least in part, by differences in drug disposition. To investigate whether reversible interactions with plasma constituents may be a contributing factor in such differences, the binding of a number of model drugs was studied in plasma obtained from healthy Caucasian and Chinese subjects (n= 8 in each group). The unbound fractions of drugs binding to sites I and II on albumin (warfarin, diazepam, and salicylic acid) were similar in the two groups, and there was no difference in the plasma albumin concentration. By contrast, the percentages of unbound diphenhydramine (26.40% ± 6.46% versus 18.30% ± 4.31, mean ± SD) and propranolol (13.81% ± 1.33% versus 11.68% ± 2.37) were significantly (p<0.05) higher in Chinese subjects compared to Caucasians. A 30% difference was also observed in the nonlinear binding of disopyramide. These basic drugs interact with both α1‐acid glycoprotein and albumin, and the lower binding was associated with a lower plasma concentration of the acute‐phase reactant in Chinese subjects. Kinetic analysis of the disopyramide binding isotherm was also suggestive of reduced binding capacity with no change in binding affinity. The reason for the racial difference in the α1‐acid glycoprotein level is unknown; however, for drugs extensively bound to this glycoprotein the resulting difference in unbound fraction would be expected to have predictable pharmacokinetic consequences that may result in differences in responsiveness. Determination of plasma binding, especially of drugs interacting with α1‐acid glycoprotein, should therefore be an essential component of comparative studies in subjects of different races.Clinical Pharmacology and Therapeutics(1990)48,10–17; doi:10.

ISSN:0009-9236    

DOI:10.1038/clpt.1990.111

年代:1990

数据来源: WILEY

摘要:

The pharmacokinetics and pharmacodynamics of atracurium, a nondepolarizing neuromuscular blocking agent, were compared between morbidly obese patients and nonobese patients. Atracurium besylate (0.2 mg/kg) was administered intravenously as a bolus to patients who had received anesthesia. The force of contraction of the adductor pollicis was measured and plasma samples were collected for a 2‐hour period. The concentrations of atracurium and its major end product, laudanosine, were determined by use of a chromatographic method. The pharmacokinetic‐pharmacodynamic relationship was characterized by use of several models. No difference was observed between obese patients and nonobese patients in atracurium elimination half‐life (19.8 ± 0.7 versus 19.7 ± 0.7 minutes), volume of distribution at steady state (8.6 ± 0.7 versus 8.5 ± 0.7 L), and total clearance (444 ± 29 versus 404 ± 25 ml/min). However, if values were expressed on a total body weight basis, there was a difference between obese and nonobese patients in the volume of distribution at steady state (0.067 versus 0.141 L/kg) and total clearance (3.5 ± 0.2 versus 6.6 ± 0.5 ml/min/kg). Although atracurium concentrations were consistently higher in obese patients than in nonobese patients, there was no difference in the time of recovery from neuromuscular blockade between the two groups. Consequently, the median effective concentration was higher in obese than in nonobese patients (470 ± 46 versus 312 ± 33 ng/ml).Clinical Pharmacology and Therapeutics(1990)48,18–25; doi:10.

ISSN:0009-9236    

DOI:10.1038/clpt.1990.112

年代:1990

数据来源: WILEY

摘要:

Single doses of 1 gm 5‐aminosalicylic acid (5‐ASA) suspension was administered to 24 healthy volunteers during both fasting and fed conditions. For subjects in a fasting state, plasma 5‐ASA and acetyl 5‐ASA concentrations peaked rapidly 1 hour after dosing to 14.72 μg/ml and 11.4 μg/ml, respectively. The elimination half‐life of 5‐ASA was 51.9 minutes, whereas the acetyl 5‐ASA half‐life could not be determined. A mean of 78.3% of the dose was excreted in the urine, with 5‐ASA accounting for 21.2% of the dose and acetyl 5‐ASA accounting for the balance. Only 11.3% of the dose was eliminated in the feces, consisting mostly of acetyl 5‐ASA. Food coadministration reduced 5‐ASA and acetyl 5‐ASA systemic relative bioavailability to 44% and 76%, respectively, compared with the fasting treatment. Urinary excretion of the salicylates was reduced to 46.8%, and fecal salicylate elimination increased almost 100%– to 24.2% of the total dose.Clinical Pharmacology and Therapeutics(1990)48,26

ISSN:0009-9236    

DOI:10.1038/clpt.1990.113

年代:1990

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1990)48,33–33; doi:10.1038/clpt.1990.1

ISSN:0009-9236    

DOI:10.1038/clpt.1990.114

年代:1990

数据来源: WILEY

摘要:

The effect of olestra, a nonabsorbable, noncaloric fat replacement, on the absorption and efficacy of a highly lipophilic oral contraceptive was investigated in a double‐blind, placebo‐controlled crossover study with 28 women. Subjects consumed 18 gm/day olestra for 28 days while taking an oral contraceptive containing 300 μg of norgestrel and 30 μg ethinyl estradiol (Lo/Ovral‐28). Blood taken on days 12 to 14 of the treatment cycles was analyzed for ethinyl estradiol and norgestrel. There was no statistically significant difference in time to attain maximum concentration, maximum concentration, or area under the concentration‐time curve between the olestra and placebo treatments for either drug component. Measurements of serum progesterone indicated that olestra ingestion did not reduce efficacy as indicated by ovulation. The data show that ingestion of 18 gm/day olestra did not affect the absorption or efficacy of the highly lipophilic oral contraceptive.Clinical Pharmacology and Therapeutics(1990)48,34–40; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1990.115

年代:1990

数据来源: WILEY

摘要:

The hemodynamic effects of quinapril, a novel nonsulfhydryl‐containing angiotensin‐converting enzyme (ACE) inhibitor, were assessed in 10 patients with mild‐to‐moderate essential hypertension. Compared with placebo, quinapril (20 mg) administered twice daily for 4 weeks significantly lowered blood pressure by decreasing total peripheral resistance without producing tachycardia, an increase in cardiac output, or a rise in plasma catecholamines. Quinapril significantly reduced renal, but not forearm, vascular resistance. Renal blood flow, glomerular filtration rate, and filtration fraction remained unchanged. Left ventricular wall stress was markedly reduced by quinapril, but during the relatively short treatment period, only a nonsignificant trend toward reduction in left ventricular mass was observed. These findings suggest that quinapril is an effective antihypertensive agent that lowers peripheral resistance without increasing cardiac output or disturbing autoregulation of renal hemodynamics.Clinical Pharmacology and Therapeutics(1990)48,41–49; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1990.116

年代:1990

数据来源: WILEY

摘要:

Ten patients with chronic occlusive arteriosclerosis received single oral doses of 100, 200, 400, 800, and 1200 mg pentoxifylline in a single‐blind, placebo‐controlled study. Blood samples were drawn at baseline and at 2 hour intervals for 6 hours. Drug and metabolite levels, as well as red cell filterability (deformability), were determined on all blood samples. Statistically significant dose‐response increases of red cell filterability were found 4 and 6 hours after oral medication with the dosages of 200 to 1200 mg pentoxifylline. These changes were proportional to the plasma levels of pentoxifylline and metabolites 1 and 5 of this agent. Attempts were made to develop a suitable animal‐screening method for agents with similar activity and to determine whether red blood cells in the absence of disease‐related abnormalities may respond to this type of therapy. Five healthyMacaca arctoidesmonkeys were given 24 mg/kg pentoxifylline intravenously, and measurable but lesser increases in red cell deformability were recorded than in the patients.Clinical Pharmacology and Therapeutics(1990)48,50–56; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1990.117

年代:1990

数据来源: WILEY

摘要:

To compare the effects of the stimulant drugs dextroamphetamine and methylphenidate on urinary and plasma monoamines and metabolites within the same clinical sample, thirty‐one children with attention‐deficit disorder with hyperactivity were treated with dextroamphetamine (up to 1.5 mg/kg/day), methylphenidate (up to 3.0 mg/kg/day), and placebo in an 11‐week double‐blind crossover trial. As expected, both drugs showed striking clinical efficacy, and within a subsample of the group, earlier findings were confirmed, that dextroamphetamine but not methylphenidate lowered urinary and plasma 3‐methoxy‐4‐hydroxyphenylglycol and whole body norepinephrine turnover, and that urinary and plasma concentration of homovanillic acid was unaltered by either drug. Methylphenidate but not dextroamphetamine increased plasma norepinephrine. Urinary epinephrine and metanephrine were increased with both drugs, but this increase did not correlate significantly with clinical improvement.Clinical Pharmacology and Therapeutics(1990)48,57–66; doi:10.10

ISSN:0009-9236    

DOI:10.1038/clpt.1990.118

年代:1990

数据来源: WILEY

摘要:

We compared acute hemodynamic, hormonal, and natriuretic responses to a single oral dose of captopril (50 mg) versus enalapril maleate (10 mg) administered to eight patients with biopsy‐proved liver cirrhosis. Although the two angiotensin‐converting enzyme (ACE) inhibitors lowered(p<0.05) blood pressure with no change in heart rate during the early postdose period, captopril produced a greater(p<0.05) hypotensive effect than did enalapril. Enalapril caused a greater(p<0.01 to 0.05) ACE inhibition than did captopril during the 2‐ to 48‐hour postdose period. Plasma renin activity increased(p<0.05) with the two drugs and returned toward baseline by 12 hours after administration. Plasma aldosterone levels, elevated before drug administration, were decreased by the two drugs in a stepwise fashion, but the suppressive effect was greater (p<0.01 orp<0.05) after captopril than after enalapril. Natriuresis was greater (p<0.05) during the first 24‐hour period after enalapril than after captopril. The findings indicate that the acute pharmacodynamic responses to the two ACE inhibitors differ in patients with liver cirrhosis. However, the mechanism(s) of the divergent effects of the two drugs and the clinical implications remain obscure from this single‐dose study.Clinical Pharmacology and Therapeutics(1990)48,67–75; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1990.119

年代:1990

数据来源: WILEY