摘要:

There is controversy as to whether acute tolerance develops to the principal effects of cocaine in humans. The studies described here demonstrate the phenomenon of acute tolerance to cocaine chronotropic and subjective effects and the rate and extent of tolerance development. Stable plasma cocaine concentrations were produced and then maintained in volunteer cocaine users by administering an intravenous cocaine injection followed by a cocaine infusion designed to compensate for the plasma clearance of cocaine. The euphoric effect (high) intensified to a peak at about 1 hour and then declined toward baseline at 4 hours despite the presence of constant plasma cocaine levels. The chronotropic effect reached a peak within 10 minutes and then declined, with a half‐life of 31 ± 13 (mean ± SD) minutes toward a plateau at 33% ± 21% of its peak intensity. Tolerance development was quantified as an exponential process, with a rate constant (tolerance factor) accounting for the progressive alteration of the cocaine concentration‐effect relationship.Clinical Pharmacology and Therapeutics(1988)44,1–8; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1988.104

年代:1988

数据来源: WILEY

摘要:

Drug elimination in patients sustaining serious thermal injury may be altered, resulting in an increased clearance and shortened half‐life. Nine burn and eight medical/surgical patients with normal renal function were studied prospectively. Doses were adjusted to achieve peak and trough vancomycin serum concentrations within a narrow range. No significant difference between the groups was noted in terms of demographic characteristics, creatinine clearance, or vancomycin serum concentrations. However, the difference in daily dose needed to maintain the specified serum concentrations was significantly greater for burn patients (p<0.02). Burn patients also had to be dosed significantly more often than medical/surgical patients to achieve peak and trough vancomycin serum concentrations within the desired range (p<0.02). The elimination half‐life in burn patients was significantly shorter than that in control patients (p<0.001). Because of the unusually high dosage requirements in burn patients, along with their poor predictability, individualization of therapy with vancomycin serum concentrations is recommended to ensure a successful therapeutic outcome.Clinical Pharmacology and Therapeutics(1988)44,9–13; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1988.105

年代:1988

数据来源: WILEY

摘要:

The effect of midazolam on α‐activity of the EEG and latency of the P‐100 of the visual evoked response (VER) was studied in six healthy subjects. Drug concentration was related to effect with the Emaxmodel that was used with either a threshold drug concentration or a sigmoid exponent. An effect compartment was included in the pharmacokinetic‐pharmacodynamic model. Four subjects showed hysteresis, and mean values of half‐lives‐keoranged from 0.26 to 0.60 hour. Mean values of EC50ranged from 42.0 to 48.1 ng/ml. Goodness of fit did not differ significantly between the sigmoid Emaxmodel and the threshold Emaxmodel. The sigmoid exponent estimated was 3.7 ± 1.8 (EEG, mean ± SD) and 2.9 ± 1.4 (VER); the threshold concentration was estimated at 15.7 ± 11.1 ng/ml (EEG) and 11.3 ± 7.0 ng/ml (VER). We conclude that the Emaxmodel adequately describes the relationship between midazolam concentration and effect and that the sigmoid exponent can be substituted by a threshold drug concentration, with a comparable fit of the model to the data.Clinical Pharmacology and Therapeutics(1988)44,14–22; doi:10.

ISSN:0009-9236    

DOI:10.1038/clpt.1988.106

年代:1988

数据来源: WILEY

摘要:

Because of recent resurgence in its consumption, the effects and health consequences of smokeless tobacco are of considerable public health interest. We studied the extent and time course of absorption of nicotine and cardiovascular effects of smokeless tobacco (oral snuff and chewing tobacco) and compared it with smoking cigarettes and chewing nicotine gum in 10 healthy volunteers. Maximum levels of nicotine were similar but, because of prolonged absorption, overall nicotine exposure was twice as large after single exposures to smokeless tobacco compared with cigarette smoking. All tobacco use increased heart rate and blood pressure, with a tendency toward a greater overall cardiovascular effect despite evidence of development of some tolerance to effects of nicotine with use of smokeless tobacco. Relatively low levels of nicotine and lesser cardiovascular responses were observed with use of nicotine gum. Adverse health consequences of smoking that are nicotine related would be expected to present a similar hazard with the use of smokeless tobacco.Clinical Pharmacology and Therapeutics(1988)44,23–28; doi:10.1038/clpt.1988.1

ISSN:0009-9236    

DOI:10.1038/clpt.1988.107

年代:1988

数据来源: WILEY

摘要:

Twelve healthy subjects received a single oral dose of theophylline, 5 mg/kg alone, and after 7 days of oral verapamil, 120 mg every 8 hours, diltiazem, 90 mg every 8 hours, and nifedipine, 20 mg every 8 hours, in randomized crossover fashion. Mean theophylline oral clearance decreased 18% and 12% after verapamil and diltiazem, respectively (p<0.05). No significant change in theophylline oral clearance was observed after nifedipine. Increases in mean theophylline half‐life were observed after verapamil (10.8 ± 3.2 hours) and diltiazem (9.9 ± 2.4 hours) (p<0.05) but not after nifedipine (8.6 ± 2.4 hours) when compared with control (8.6 ± 1.9 hours). Apparent volume of distribution was unchanged. Urinary excretion data showed that the relative formation rate constants of 3‐methylxanthine and 1,3‐dimethyluric acid were decreased during verapamil and diltiazem (p<0.05) but not during nifedipine. No change in 1‐methyluric acid excretion was observed. Increases in urinary elimination of unchanged theophylline were observed after verapamil, diltiazem, and nifedipine. The modest reduction in theophylline clearance observed after verapamil and diltiazem is not likely to produce clinically significant increases in theophylline concentrations in most patients.Clinical Pharmacology and Therapeutics(1988)44,29–34; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1988.108

年代:1988

数据来源: WILEY

摘要:

To investigate a possible interaction between norfloxacin and theophylline, eight healthy nonsmoking volunteers (mean age 27 ± 5.3 years) were administered aminophylline, 5 mg/kg, before and after a 6‐day course of norfloxacin, 400 mg every 12 hours, and changes in pharmacokinetic parameters were measured and compared. Norfloxacin induced significant decreases in theophylline clearance (14.9%;p<0.01) and the terminal phase slope (13.3%;p<0.02) and increased the AUC (16.6%;p<0.01). The apparent volume of distribution at steady state was unchanged. The greatest norfloxacin‐induced individual change in theophylline clearance was a reduction of 28.6%. Given these findings, we advise that, for patients who are treated with theophylline and are subsequently treated with norfloxacin, adjustment of the theophylline dosage may be necessary in some patients to minimize the risk of theophylline toxicity.Clinical Pharmacology and Therapeutics(1988)44,35–38; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1988.109

年代:1988

数据来源: WILEY

摘要:

Disposition of pentopril was studied in 15 male volunteers with varying renal functions. Mild to moderate compromise in renal function did not demonstrate any appreciable changes in plasma concentration of pentopril, the prodrug ester of the active angiotensin–converting enzyme (ACE) inhibitor CGS 13934. This is consistent with the known elimination pattern for pentopril, which is eliminated primarily by hydrolysis to the active inhibitor. In contrast, the plasma concentration of the active ACE inhibitor was sensitive to moderate changes in renal function. Because of the reciprocal relationship of AUC and clearance, AUC did not change to any appreciable extent until creatinine clearance (CLCR) dropped to about 50 ml/min. Below 50 ml/min of CLCR, AUC and half‐life increased sharply with reduced kidney function. Because of the significant contribution of the renal secretion process to total renal elimination of both pentopril and the active metabolite, prediction of renal clearance from CLCRwas poor at relatively normal kidney function (CLCR>80 ml/min). However, renal secretory clearances for both pentopril and metabolite were well correlated top‐aminohippuric acid clearance. In patients with moderately compromised renal function (glomerular filtration rate<40 ml/min), tubular secretion rate of creatinine approaches its glomerular filtration rate and hence CLCRcould be used as a predictor of renal clearance and other disposition parameters. Plasma ACE activity also demonstrated prolonged inhibition with decreased renal function. Based on the prolonged blockade of plasma ACE activity, some correction in dose or dosing interval is anticipated in patients with moderately compromised renal function (CLCR<50 ml/min).Clinical Pharmacology and Therapeutics(1988)44,39–48; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1988.110

年代:1988

数据来源: WILEY

摘要:

Fenoldopam, a dopamine‐1 receptor agonist, has been reported to exhibit α‐adrenoceptor—blocking actions in intact and isolated animal preparations. To determine whether α‐adrenoceptor blockade contributes to its antihypertensive properties in humans, the effects of fenoldopam on the pressor responses to norepinephrine and angiotensin II were compared in eight normal volunteers. Fenoldopam (0.5 μg/kg/min) shifted the dose‐response curves for both agonists to the right (p<0.05). Dose ratios for an increase in mean blood pressure of 10 mm Hg were 3.3 ± 0.9 for norepinephrine and 3.2 ± 0.6 for angiotensin II (pnot significant). Consequently, fenoldopam is not a selective a‐adrenoceptor antagonist at therapeutic concentrations in humans.Clinical Pharmacology and Therapeutics(1988)44,49–54; doi:10

ISSN:0009-9236    

DOI:10.1038/clpt.1988.111

年代:1988

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1988)44,55–55; doi:10.1038/clpt.1988.1

ISSN:0009-9236    

DOI:10.1038/clpt.1988.112

年代:1988

数据来源: WILEY

摘要:

The ability of cumulative dose‐response techniques to obtain accurate data is most likely limited by redistribution and elimination of the drug during the study period. Therefore the usefulness of these techniques would be improved by replacing the amount of drug lost. This hypothesis was assessed for the intermediate‐duration neuromuscular blockers vecuronium and atracurium, and calculations were made based on a pharmacokinetic model with an effect compartment. Sixty patients received either single doses (SD) (n = 36), cumulative doses (CD) (n = 12), or CD of vecuronium or atracurium with an infusion (CDI) to replace eliminated or redistributed drug (n = 12). The force of contraction of the adductor pollicis muscle in response to train‐of‐four stimulation was measured and recorded. Linear regressions were obtained between the logit transformation of neuromuscular blockade at the adductor pollicis and log dose. The potencies obtained with all three methods were within 20% of each other. For vecuronium the ED90was (mean ± SE) 0.034 ± 0.002 (SD), 0.037 ± 0.003 (CD), and 0.036 ± 0.003 mg/kg (CDI). For atracurium the ED90was 0.175 ± 0.009 (SD), 0.206 ± 0.019 (CD), and 0.179 ± 0.015 mg/kg (CDI). Calculated values corresponded well with measured values. The calculations predicted that the agreement between single‐ and cumulative‐dose techniques would be improved if (1) the dose increment was increased, (2) the elimination half‐life was increased above 20 minutes, or (3) an infusion was added. It is concluded that for muscle relaxants of intermediate durations of action, the use of an infusion to compensate for drug lost by redistribution or elimination improves accuracy of the cumulative‐dose technique.Clinical Pharmacology and Therapeutics(1988)44,56–64;

ISSN:0009-9236    

DOI:10.1038/clpt.1988.113

年代:1988

数据来源: WILEY