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1. |
On the significance of host factors that affect drug disposition |
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Clinical Pharmacology&Therapeutics,
Volume 31,
Issue 1,
1982,
Page 1-7
Elliot S Vesell,
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摘要:
Reports on drug disposition in man often overemphasize statistical analyses or correlation coefficients at the expense of clear statements on the biological meaning of an experiment. Moreover, the results of many such studies are presented as though they were immutable. In reality, the levels of statistical significance often depend on, and are intimately related to, numerous host factors. Results can fall anywhere within a broad spectrum of values determined by the host factors of the subjects selected for investigation. The investigator's objectives determine whether subjects are selected for uniformity or heterogeneity of these host factors. Since only a small number of subjects can be studied, it is unlikely that all critical host factors will be represented. Therefore, studies repeated elsewhere may not duplicate subject host factors with sufficient precision to allow a similar outcome. Thus, a full description of critical host factors is required for all subjects who serve in studies on drug disposition. This requirement is particularly important because many subjects suffering from diseases exhibit simultaneous changes in critical host factors, thereby modifying the dosage requirements for drug therapy. The number of host factors recognized as capable of influencing drug disposition has risen due to recent discoveries in this active field.Clinical Pharmacology and Therapeutics(1982)31, 1–7; doi:10.1038/clpt.1982
ISSN:0009-9236
DOI:10.1038/clpt.1982.1
年代:1982
数据来源: WILEY
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2. |
Metoprolol withdrawal phenomena: Mechanism and prevention |
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Clinical Pharmacology&Therapeutics,
Volume 31,
Issue 1,
1982,
Page 8-15
Robert E Rangno,
Serge Langlois,
Alfred Lutterodt,
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摘要:
Eight patients taking metoprolol (300 mg/day) for essential hypertension were studied after abrupt withdrawal and placebo replacement of the drug. A 52% average rebound increase in cardiac chronotropic sensitivity to isoproterenol and 15% rebound rise in resting heart rate occurred in all patients between 2 to 8 days after metoprolol withdrawal (P<0.05). Holter monitoring showed no associated arrhythmia. A transient increase in blood pressure occurred in one patient and withdrawal‐like symptoms were noted in three patients. There were no meaningful changes in plasma norepinephrine, epinephrine, thyroxine, or triiodothyronine. Seven of the eight patients were again studied serially after the same metoprolol dosing, during a prolonged low‐dose withdrawal schedule (50 mg/day for 10 days) and during placebo. Prolonged low dose before complete metoprolol withdrawal decreased but did not completely prevent the changes observed after abrupt withdrawal. The observed rebound of cardiac beta‐adrenergic sensitivity may have application to the mechanism and prevention of the beta‐blocker syndrome in patients with angina.Clinical Pharmacology and Therapeutics(1982)31, 8–15; doi:10.1038/c
ISSN:0009-9236
DOI:10.1038/clpt.1982.2
年代:1982
数据来源: WILEY
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3. |
Estimation of sympathetic activity in essential hypertension |
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Clinical Pharmacology&Therapeutics,
Volume 31,
Issue 1,
1982,
Page 16-22
M J Brown,
F J M Lhoste,
C Zamboulis,
P W Ind,
D A Jenner,
C T Dollery,
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摘要:
The estimation of sympathetic nervous activity by measurement of plasma norepinephrine (NE) concentration assumes a constant relation between this and the synaptic cleft concentration. This assumption would be incorrect if the clearance of plasma NE could be varied without affecting its removal from the synaptic cleft, so we compared the clearance of plasma NE in mild hypertensives and normal subjects by measurement of its plasma concentration during a 0.5‐hr infusion at 0.07 μg/kg/min; there were no differences. The simultaneous infusion of isoproterenol, 0.02 μg/kg/min, led to an increase in heart rate and NE clearance. There was partial inhibition of catechol‐O‐methyltransferase by a single oral dose of alpha‐methyldopa, 250 mg, which reduced the clearance of both catecholamines (CAs) by about 20%. After the end of the infusions containing isoproterenol, the tachycardia persisted for more than 1 hr and declined more slowly in the hypertensives than the normals. In contrast, plasma concentrations of both CAs returned to basal values within a few minutes. The persistent tachycardia may be due to rerelease of isoproterenol into the synaptic cleft, since stimulation of sympathetic activity by assumption of the erect posture was associated with an exaggerated increase in heart rate (by 48/min after infusion and 23/ min before infusion). The study therefore suggests that synaptic cleft and plasma CA concentrations can be independently manipulated and the relation between them may be different in hypertensive patients and normal control subjects.Clinical Pharmacology and Therapeutics(1982)31, 16–22; doi:10.1038
ISSN:0009-9236
DOI:10.1038/clpt.1982.3
年代:1982
数据来源: WILEY
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4. |
Sparteine metabolism in Canadian Caucasians |
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Clinical Pharmacology&Therapeutics,
Volume 31,
Issue 1,
1982,
Page 23-29
A Vinks,
T Inaba,
S V Otton,
W Kalow,
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摘要:
The capacity for sparteine (SP) metabolism was determined in 48 Caucasian subjects by measuring amounts of drug and dehydrogenated metabolites in urine after an oral dose of SP sulfate. Three phenotypes were recognized and were assumed to represent individuals homozygous for poor SP oxidation (group III) and those heterozygous (group II) and homozygous (group I) for extensive SP oxidation. Separation of groups I and II, although incomplete, was improved by alterations in the published analytic procedure. The pattern of deviations from the normal distribution was similar for both dehydrosparteine metabolites. This supports the hypothesis of a common intermediate, the formation of which is monogenically controlled. Correlation analysis of the two metabolites indicates the possibility of further metabolism of 5‐dehydrosparteine.Clinical Pharmacology and Therapeutics(1982)31, 23–29; doi:10.1038/clpt.19
ISSN:0009-9236
DOI:10.1038/clpt.1982.4
年代:1982
数据来源: WILEY
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5. |
Sex differences in absorption kinetics of sodium salicylate |
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Clinical Pharmacology&Therapeutics,
Volume 31,
Issue 1,
1982,
Page 30-37
Stasia L Miaskiewicz,
Carol A Shively,
Elliot S Vesell,
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摘要:
Sodium salicylate in aqueous solution (9 mg/kg) was given by oral and intravenous routes to normal male and female subjects. Because the bio availability of salicylate was complete, salicylate was given orally in all subsequent experiments. There were sex differences in time required to attain peak salicylate concentration (tmax), but not in maximum plasma salicylate concentration (Cmax). There were no sex differences in apparent volume of distribution, plasma salicylate clearance, or area under the concentration‐time curve. In female subjects, tmaxtended to reach a nadir at the middle of the menstrual cycle, when gastric emptying time is shortest, whereas Cmaxremained relatively unchanged throughout the menstrual cycle. Equilibrium dialysis studies on the binding of sodium salicylate and of14C‐racemic warfarin to plasma from 25 normal male and 25 normal female subjects of similar age disclosed no sex differences either in the extent of binding of these drugs or in serum albumin concentration. The possibility of sex differences in rates of gastrointestinal absorption of other drugs should be investigated.Clinical Pharmacology and Therapeutics(1982)31, 30–37; doi:10.1038/clpt.
ISSN:0009-9236
DOI:10.1038/clpt.1982.5
年代:1982
数据来源: WILEY
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6. |
Antipyrine disposition in milk and saliva of lactating women |
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Clinical Pharmacology&Therapeutics,
Volume 31,
Issue 1,
1982,
Page 38-44
Cheston M Berlin,
Elliot S Vesell,
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摘要:
Widely used to study hepatic drug metabolism, antipyrine rapidly distributes in total body water. Antipyrine distribution was studied in seven lactating women. Duration of lactation ranged from 2 to 19 mo. In all subjects the drug was rapidly absorbed; in five women peak concentrations were attained in milk and saliva by 1 hr and in the other two women by 3 hr (first point at which collections were made). In two women in whom antipyrine was measured at 10‐min intervals during the first hour, peak concentrations in both milk and saliva were attained by 10 min after antipyrine. The time course for antipyrine disappearance from milk paralleled that from saliva for each subject. Antipyrine half‐life (t½) varied from 5.6 to 20.3 hr for saliva (x± SD = 11.5 ± 4.8) and from 5.7 to 21.7 hr for milk (x± SD = 11.6 ± 5.4). In the two women with the shortest salivary antipyrine t½ (5.6 and 7.5 hr), antipyrine was readministered many months later, after they had stopped lactating. The salivary antipyrine t½ rose from 5.6 to 13.3 hr in one subject and from 7.5 to 14.6 hr in the other. The corresponding decrease in antipyrine clearance was 0.93 to 0.55 and 1.41 to 0.60 ml/min/kg. This observation suggests that in some subjects lactation may influence drug metabolism. The amount of antipyrine available to each nursing infant was estimated by assuming that the infant nursed 3 ounces every 4 hr for 24 hr after maternal antipyrine administration. The amount of antipyrine available to the nursing infant was calculated to range from 3.0 to 11.1 mg (x± SD — 6.4 ± 2.9 mg) or from 0.25% to 1.07% (x± SD = 0.59 ± 0.29%) of the maternal dose.Clinical Pharmacology and Therapeutics(1982)31, 38–44; doi:
ISSN:0009-9236
DOI:10.1038/clpt.1982.6
年代:1982
数据来源: WILEY
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7. |
Age and renal clearance of cimetidine |
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Clinical Pharmacology&Therapeutics,
Volume 31,
Issue 1,
1982,
Page 45-50
Dennis E Drayer,
John Romankiewicz,
Beverly Lorenzo,
Marcus M Reidenberg,
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摘要:
In 35 patients (ages 20 to 86 yr) receiving cimetidine therapeutically two serum samples and all urine formed in the interim were collected for analysis of cimetidine by high‐pressure liquid chromatography and for creatinine. Cimetidine clearance decreased with age. The extrapolated 6‐hr serum concentration of cimetidine per unit dose, after intravenous cimetidine, increased with age of the patients. The ratio of cimetidine clearance to creatinine clearance (Rc) averaged 4.8 ± 2.0, indicating net tubular secretion for cimetidine. Rc seemed to be independent of age and decreased with increasing serum concentration of cimetidine, suggesting that secretion of cimetidine is a saturable process. There was only one case of dementia possibly due to cimetidine (with a drug level of 1.9μg/ml 6 hr after a dose) in a group of 13 patients without liver or kidney disease who had cimetidine levels above 1.25 μg/ml. Thus, high cimetidine levels alone do not always induce dementia.Clinical Pharmacology and Therapeutics(1982)31, 45–50; doi:10.1038/cl
ISSN:0009-9236
DOI:10.1038/clpt.1982.7
年代:1982
数据来源: WILEY
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8. |
Altered hydroxydesipramine concentrations in elderly depressed patients |
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Clinical Pharmacology&Therapeutics,
Volume 31,
Issue 1,
1982,
Page 51-55
Isamu Kitanaka,
Richard J Ross,
Neal R Cutler,
Anthony P Zavadil,
William Z Potter,
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摘要:
Recent reports demonstrate that hydroxy metabolites of desipramine (DMI) have pharmacologic activity and do not just produce side effects. In patients treated with DMI, we determined the ratio of 2‐hydroxydesipramine (2‐OH‐DMI) to drug at steady state. The ratios in the elderly patients were higher than in younger patients, and whereas plasma levels of 2‐OH‐DMI increased with age, urinary clearances decreased. The known decrease in glomerular filtration with age may explain the selective increase of 2‐OH‐DMI concentration in the elderly.Clinical Pharmacology and Therapeutics(1982)31, 51–55; doi:10.
ISSN:0009-9236
DOI:10.1038/clpt.1982.8
年代:1982
数据来源: WILEY
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9. |
Amiloride in primary hyperaldosteronism |
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Clinical Pharmacology&Therapeutics,
Volume 31,
Issue 1,
1982,
Page 56-61
George T Gritting,
Alan G Cole,
Steven A Aurecchia,
Bruce H Sindler,
Pavel Komanicky,
James C Melby,
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摘要:
Amiloride is a potassium‐sparing diuretic used in spontaneous and diuretic‐induced hypokalemia. The effect of amiloride was studied prospectively in 12 patients with primary hyperaldosteronism. Four patients had unilateral adrenal adenomas and eight had bilateral adrenal hyperplasia. All patients were hypertensive and their mean plasma potassium levels were low. Amiloride, 10 to 40 mg daily, was given for 6 mo. Mean plasma potassium levels rose (0.96 mEq/l, P<0.001) and remained normal throughout the study without potassium supplementation. Mean blood pressure was lowered by amiloride (22/10 mm Hg, P<0.001) but normotension required concomitant antihypertensive therapy in most patients. No significant adverse clinical or laboratory experiences could be directly attributed to amiloride therapy. There was no correlation between the response to therapy and the plasma aldosterone levels, aldosterone secretion rate, or presence of a unilateral adrenal adenoma. Our study demonstrates the efficacy of amiloride in the correction of hypokalemia and amelioration of hypertension in primary hyperaldosteronism.Clinical Pharmacology and Therapeutics(1982)31, 56–61; doi:10.1038/clpt.
ISSN:0009-9236
DOI:10.1038/clpt.1982.9
年代:1982
数据来源: WILEY
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10. |
Alpha1‐acid glycoprotein concentration and protein binding in trauma |
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Clinical Pharmacology&Therapeutics,
Volume 31,
Issue 1,
1982,
Page 62-67
David J Edwards,
David Lalka,
Frank Cerra,
Richard L Slaughter,
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摘要:
α1‐Acid glycoprotein (AAG) concentrations were measured every 2 to 3 days in eight trauma patients and seven healthy subjects for approximately 3 wk. Mean AAG concentrations in the trauma patients rose from 100 mg/dl to a peak value of 243 mg/dl at 10 to 14 days. AAG levels averaged more than 200 mg/dl at 15 to 21 days. Mean AAG concentration in healthy subjects was 70 mg/dl with little inter‐ or intraindividual variability. Lidocaine was added to all serum samples from four of the patients and to selected samples from all of the healthy subjects and protein binding was determined. The binding ratio (bound concentration/free concentration) correlated strongly with AAG concentration in the trauma patients (r = 0.92), in the healthy subjects (r = 0.84), and in both groups combined (r = 0.96). AAG concentration and binding ratio for each of the four patients individually also correlated (P<0.05 in all cases). The change in free fraction associated with this increase in AAG was approximately doubled in each patient. Similar findings with drugs commonly used in trauma patients would be expected to alter serum concentration‐response relationships significantly.Clinical Pharmacology and Therapeutics(1982)31, 62–67; doi:10.1038/clp
ISSN:0009-9236
DOI:10.1038/clpt.1982.10
年代:1982
数据来源: WILEY
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