摘要:

Six subjects were evaluated for the effect of quinine, the 1‐isomer of quinidine, on digoxin pharmacokinetics. A 1.0‐mg intravenous digoxin dose was given before and during quinine administration, followed by the measurement of digoxin serum and urine concentrations for 96 hr after each dose. Quinine reduced digoxin total body clearance by 26% from 2.98 to 2.22 ml/min/kg (p<0.03). Digoxin elimination half‐life (t½) was lengthened from 34.2 to 51.8 hr, reflecting a 32% decrease in digoxin elimination rate constant (p<0.003). Quinine did not reduce digoxin renal clearance or any volumes of distribution. The amount of digoxin excreted into the urine increased from x̄ = 628.29 μg to x̄ = 772.52 μg (p<0.02). Digoxin nonrenal clearance decreased an average of 55% from 1.2 to 0.55 ml/min/kg (p<0.05). These results suggest that quinine alters digoxin metabolism or biliary secretion, reducing digoxin total body clearance by a mechanism that is qualitatively similar, but quantitatively different, from quinidine.Clinical Pharmacology and Therapeutics(1980)28,425–430; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1980.183

年代:1980

数据来源: WILEY

摘要:

The efficacy on premature ventricular contractions (PVCs) of tocainide 600 mg three times daily and of quinidine sulfate 300 mg four times daily administered for 8 wk versus placebo administered for 6 wk was determined in 41 patients. Neither the subjects nor the interpreter of the Holter recordings knew which medication had been used. Adverse effects occurred in 14 of 22 patients (64%) on tocainide and in nine of 19 (47%) on quinidine. Adverse effects caused 13 of 22 patients (59%) on tocainide and six of 19 (32%) on quinidine to discontinue medication. Reduction of PVCs ≥ 75% over placebo occurred in one of nine patients (11%) on tocainide and in six of 13 (46%) on quinidine. By Lown's classification, a reduction in one grade of PVCs occurred in two of nine patients (22%) on tocainide and in eight of 13 (62%) on quinidine. Neither tocainide nor quinidine has a high incidence of efficacy and a low incidence of adverse effects but, in the doses used, quinidine was more effective, benefited a larger proportion of patients, and induced fewer adverse effects than tocainide.Clinical Pharmacology and Therapeutics(1980)28,431–435; doi:10.1038/clpt.1980

ISSN:0009-9236    

DOI:10.1038/clpt.1980.184

年代:1980

数据来源: WILEY

摘要:

The hemodynamic effects of a single oral dose of 80 mg pentaerythritol tetranitrate (PETN) were determined over a 5‐hr period in 16 patients with chronic congestive heart failure. PETN decreased (p<0.05) pulmonary capillary wedge pressure (27 to 18 mm Hg), right atrial pressure (15 to 9 mm Hg), mean systemic arterial pressure (89 to 80 mm Hg), and systemic vascular resistance (1,812 to 1,466 dynes · sec · cm−5). There were increases (p<0.01) in cardiac index (2.0 to 2.31/m2/min), stroke volume index (24 to 28 ml/m2), and stroke work index (25 to 31 gm‐m/m2). Peak reduction in pulmonary capillary wedge pressure occurred 2 hr after PETN and hemodynamic effects were still apparent at 5 hr. In nine patients in whom left and right ventricular ejection fractions were determined by radionuclide ventriculography before and after PETN, no changes were found in left ventricular ejection fraction (0.20 to 0.22, p = NS) although there was a modest increase in right ventricular ejection fraction (0.29 to 0.34, p<0.05). The data indicate that oral PETN may induce beneficial effects on preload and afterload in congestive cardiac failure that may last 5 or more hours.Clinical Pharmacology and Therapeutics(1980)28,436–440; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1980.185

年代:1980

数据来源: WILEY

摘要:

We have reported that clonidine (CLON) reduces basal norepinephrine (NE) levels but has no effect on basal epinephrine (E) levels. To study the effects of CLON on stimulated NE and E secretion, six normal men received a single dose of CLON followed by induction of hypoglycemia with insulin. Despite the presence of a mean hypoglycemic nadir of 44 mg/100 ml, there was no rise in E and NE levels during CLON treatment. To determine the effects of such catecholamine inhibition on the counterregulation of hypoglycemia, additional experiments were performed since the mean glucose nadir during CLON in the initial studies was slightly (9 mg/100 ml) less deep than in controls. When subjects on CLON received higher doses of insulin, glucose responses were identical to control responses; CLON still reduced the 0 to 60‐min catecholamine response by 83% (p<0.02). Glucagon secretion was not impaired, but CLON blunted the early rate of glucose recovery in the first 15 min after the glucose nadir. We conclude that CLON inhibits the catecholamine (but not the glucagon) rise during insulin‐induced hypoglycemia. Selective inhibition of catecholamine secretion does not inhibit the glucogan response but leads to definite, although transient, inhibition of glucose recovery after hypoglycemia.Clinical Pharmacology and Therapeutics(1980)28,441–448; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1980.186

年代:1980

数据来源: WILEY

摘要:

Eight outpatients on long‐term hemodialysis receiving propranolol therapy were studied on a nondialysis day, 11 ± 1 hr after the last dose. Steady‐state daily dosage of propranolol averaged 225 ± 36 mg (range, 80 to 400). Plasma concentrations of propranolol and three of its metabolites were measured by gas chromatography–mass spectrometry (x̄ ± SEM): propranolol, 47 ± 17 ng/ml; propranolol glucuronide, 2,119 ± 597 ng/ml; 4‐hydroxypropranolol glucuronide, 789 ± 149 ng/ml; and naphthoxylactic acid, 4,357 ± 727 ng/ml. The plasma levels of these metabolites were 18, 20, and 29 times, respectively, as high as in patients with normal renal function and correlated well with the dose of propranolol. The total concentration of these metabolites exceeded the concentration of propranolol by 239 times (range 74 to 476). Four long‐term hemodialysis patients on propranolol were hospitalized to ensure compliance. Plasma levels of propranolol and of the three metabolites were followed during a dosage interval. Plasma propranolol levels correlated well with dose (r = 0.94) and declined with approximately normal half‐lifes of 3.2 to 5.4 hr. There was little variation in the extremely high plasma levels of the three metabolites during a dosage interval. The total metabolite to propranolol plasma concentration ratio in these four patients ranged from 109 to 705. The correlation between total metabolite concentrations and propranolol dose was striking (r = 0.997). Massive retention of propranolol metabolites occurs uniformly in uremia, is highly predictable from the dose, and could have important clinical implications.Clinical Pharmacology and Therapeutics(1980)28,449–455; doi

ISSN:0009-9236    

DOI:10.1038/clpt.1980.187

年代:1980

数据来源: WILEY

摘要:

The pattern of excretion of urinary theophylline and theophylline metabolites were studied in three groups of patients (premature neonates, children, and adults). When adjusted to a standard dose of 10 mg/kg/day to allow valid comparison between groups, differences in mean corrected trough plasma theophylline concentrations (corrected Cp) were found that were of similar magnitude to differences reported in theophylline clearance in these groups. Despite the lower corrected Cp in children, urinary theophylline metabolite patterns were similar in adults and children, indicating that the increased clearance in children is not associated with induction of a specific metabolic pathway. In premature neonates, only unchanged theophylline and caffeine were found in urine, indicating the absence of oxidative pathways for theophylline metabolism. In both adults and children, there was high positive correlation between urinary excretion of 3‐methylxanthine (3MX) and 1‐methyluric acid (1MU). Both 3MX and 1MU correlated negatively with urinary excretion of 1.3.‐dimethyluric acid (DMU). It is suggested thatN‐demethylation of theophylline to 3MX and 1MU is catalyzed by a different form of cytochrome P‐450 than that involved in the 8‐hydroxylation to DMU.Clinical Pharmacology and Therapeutics(1980)28,456–462; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1980.188

年代:1980

数据来源: WILEY

摘要:

The effects of beta adrenergic blockade on theophylline elimination were studied in nine normal subjects. Oral propranolol. 40 mg every 6 hr, induced a fall in theophylline clearance from 0.0464 ± 0.0216 to 0.0294 ± 0.0129 l/kg/hr (p<0.001). Oral metoprolol, 50 mg every 6 hr, did not reduce theophylline clearance in the group as a whole but had a reducing effect intermediate to that of propranolol on theophylline clearance in some smokers whose theophylline clearance was high initially. Beta adrenergic blockade may reduce theophylline clearance, particularly in subjects whose theophylline metabolism has been induced by cigarette smoking.Clinical Pharmacology and Therapeutics(1980)28,463–467; doi:10.1038/clpt.1980

ISSN:0009-9236    

DOI:10.1038/clpt.1980.189

年代:1980

数据来源: WILEY

摘要:

To compare the oral and intravenous disposition of bretylium tosylate in man, 10 normal male subjects were randomly assigned single doses of 5 mg/kg bretylium tosylate either orally or intravenously and crossed over 2 wk later to the opposite route (20 studies). Each experiment included sampling for drug in serum and urine over 48 hr. Bretylium tosylate was assayed by gas chromatography. Kinetic analysis provided the following mean [coefficient of variation] results: 100FPo, 22.6% [40.2%]; ClIVr, 300 ml/min [27.8%]; ClPor, 1,268 mg/min [54.8%]; ClIVB299 ml/min [31.9%]; f, 101% [8.7%]; Vdss, 3.37 l/kg [30.5%]; λIVl, 0.0510 [12.8%]; λPGl, 0.115 [52.7%] hr−1; elimination half‐life (t½) after intravenous bretylium tosylate, 13.6 hr, and after oral bretylium tosylate, 6.0 hr (harmonic means). Bretylium tosylate binding to plasma proteins in normal volunteer samples was found to be negligible. The results indicate extensive tissue binding of bretylium tosylate. Oral doses of bretylium tosylate are only partially absorbed. Bretylium tosylate is eliminated entirely by the kidneys as unchanged drug. The greater renal clearance after oral than intravenous bretylium tosylate, and the greater elimination rate constant and shorter oral bretylium tosylate t½ are of interest but no explanation is available.Clinical Pharmacology and Therapeutics(1980)28,468–478; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1980.190

年代:1980

数据来源: WILEY

摘要:

To determine the effect of dose on phenytoin bioavailability, a single intravenous 15‐mg/kg dose, single oral doses of 400, 800, and 1,600 mg, and 1,600 mg in divided doses (400 mg every 3 hr) were given to six healthy male subjects. Values of Vmax(maximum elimination rate) and Km(serum concentration at which rate of elimination is one half the maximum rate) from the intravenous dose were used to determine the extent of absorption. Although no statistically significant difference in extent of phenytoin absorption was detected, the time to reach maximum phenytoin serum concentrations increased from 8.4 hr for the 400‐mg dose and 13.2 hr for the 800‐mg dose to 31.5 hr for the 1,600‐mg dose. After the 400, 800, and 1,600‐mg doses and 1,600‐mg divided doses, the serum concentration peaks were 3.9, 5.7, 10.7, and 15.3 mg/l. It is suggested that the prolonged, but complete, absorption of large phenytoin doses is due to slow dissolution and continued absorption from the colon. Due to prolonged absorption of phenytoin, it may be necessary to use larger oral than intravenous loading doses to achieve the same maximum phenytoin serum concentrations.Clinical Pharmacology and Therapeutics(1980)28,479–485; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1980.191

年代:1980

数据来源: WILEY

摘要:

Valproic acid clearance was determined in six normal subjects during a single‐dose (250‐mg) study and multiple‐dose experiments of 500, 1,000, and 1,500 mg/day. Eight consecutive oral doses were taken at 12‐hr intervals at each dosing level. Valproate levels and protein binding were determined at steady state. Clearance declined 20% from 8.33 ± 2.44 to 6.67 ± 1.25 ml/hr/kg between the single‐dose and the 500‐mg/day steps (p = 0.05). Clearance was unchanged between the 500‐ and 1,000‐mg/day steps despite a 44% increase in mean free fraction (0.0703 ± 0.0381 vs 0.1011 ± 0.0438, p<0.05), implying a balanced opposing decline in intrinsic clearance (from 89.2 ± 71.0 to 72.0 ± 20.8 ml/hr/kg; p = 0.025). In four subjects completing the 1,500‐mg/day step, clearance increased from 6.76 ± 1.48 ml/hr/kg (1,000 mg/day) to 8.20 ± 1.62 ml/hr/kg, corresponding to a further increase in free fraction. Free fraction varied within a single dosing interval (%SD = 11% to 49%). The apparent dose‐related decline in intrinsic clearance suggests autoinhibition or saturation of metabolism.Clinical Pharmacology and Therapeutics(1980)28,486–

ISSN:0009-9236    

DOI:10.1038/clpt.1980.192

年代:1980

数据来源: WILEY