摘要:

Clinical Pharmacology and Therapeutics(1984)36,1–4; doi:10.1038/clpt.1984.1

ISSN:0009-9236    

DOI:10.1038/clpt.1984.129

年代:1984

数据来源: WILEY

摘要:

Bopindolol has β‐blocking effects for 96 hr despite a 4‐hr t½. To investigate the concentration‐effect relationship after single and repeated doses, 2‐mg oral doses were given once and then daily for 13 days to six healthy subjects. In plasma, no unchanged drug, only the hydrolysis product of bopindolol (referred to as bopindolol concentration) was detectable or could be measured up to 24 hr. Chemical assay by HPLC and determination of total active β‐adrenoceptor blocking material by radioreceptor assay gave identical results. The t½ was 4 to 5 hr. Effects, measured as reduction in exercise‐induced tachycardia (REIT) and as the isoproterenol dose ratio (DR — 1), were followed for 96 hr. The concentration of bopindolol in plasma (predicted with a one‐compartment body model) could be related to the measured effects by classic effect models for 20 t½s. Parameter estimates for kinetic end effect models did not differ after single and repeated doses. With the parameters from the single‐dose experiment, the time course of the plasma concentration and the effects after the multiple‐dose experiment could be adequately predicted for 24 and 96 hr. A deep compartment, an active metabolite, or irreversible destruction of the receptor (accounting for the persistence of the effect) could be excluded. The “dissociation constant” of 100 pmolll (from DR — 1/concentration) and the minimal effective plasma concentration (from REIT/log concentration) of 1 pmol/l suggest that enough receptors are occupied at chemically unmeasurable levels in plasma to induce an effect. The “dissociation constant” determined in vivo is of the same order as that from in vitro radioligand studies.Clinical Pharmacology and Therapeutics(1984

ISSN:0009-9236    

DOI:10.1038/clpt.1984.130

年代:1984

数据来源: WILEY

摘要:

A study with a nonspecific hydralazine assay reported that food increased hydralazine concentrations in plasma. We used a specific HPLC hydralazine assay to determine the effect of food on hydralazine blood levels and hemodynamic responses after oral hydralazine. Six subjects with uncomplicated essential hypertension were given 1 mg/kg hydralazine solution orally on two occasions at least 3 days apart. On 1 study day subjects fasted and on the other they were given a standard meal 45 min before hydralazine. Mean arterial pressure and heart rate were monitored for 2 hr before and for 4 hr after hydralazine and frequent venous blood samples were drawn for hydralazine assay. Hepatic blood flow was estimated by determination of indocyanine green clearance before food, after food, and 30 min after hydralazine. Peak blood hydralazine concentrations fell in all (46.2%±11.5%;X̄±SE) and areas under the blood hydralazine concentration/time curves fell (45.7%±9.5%) after food. This could not be explained by changes in liver blood flow. Food‐related reductions in blood levels of hydralazine were associated with reduced vasodepressor effects (41.5%±5.6%). It is possible that food increases intravascular conversion of hydralazine to hydralazine pyruvic acid hydrazone. The reduction in vasodepressor response suggests that patients with hypertension should take hydralazine at a fixed time in relation to meals.Clinical Pharmacology and Therapeutics(1984)36,14–18; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1984.131

年代:1984

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1984)36,18; doi:10.1038/clpt.1984.132

ISSN:0009-9236    

DOI:10.1038/clpt.1984.132

年代:1984

数据来源: WILEY

摘要:

Nifedipine has been reported either to decrease or not to affect digoxin elimination. We studied the effect of oral nifedipine on steady‐state digoxin concentrations and renal clearance in 20 healthy male subjects. After 2 wk of digitalization, all received digoxin, 0.375 mg a day, with placebo for 2 wk, then digoxin and nifedipine, 18.5±4 mg every 8 hr, for 2 wk, and then digoxin with placebo for 2 wk. Mean (±SD) digoxin concentrations of 0.74±0.20 and 0.75±0.25 ng/ml on placebo were not altered by nifedipine (0.77±0.23 ng/ml). Digoxin clearance was 2.2±0.6 and 2.7±0.8 ml/kg/min on placebo and 2.5±0.6 ml/kg/min on nifedipine. No change in pharmacologic effect of digoxin by nifedipine was observed, but mean blood pressure was lower and heart rates were accelerated. These data indicate that oral nifedipine does not alter digoxin concentrations or decrease renal clearance in healthy subjects.Clinical Pharmacology and Therapeutics(1984)36,19–24; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1984.133

年代:1984

数据来源: WILEY

摘要:

Our study in 10 patients with stable, exercise‐related angina under a double‐blind, placebo‐controlled protocol correlated plasma verapamil levels after single oral doses of 120 and 240 mg and exercise performance. Plasma verapamil levels peaked at 2 hr in seven patients and 4 hr in three patients and declined thereafter, with a mean plasma t½ of 3.22 and 4.54 hr after the 120‐ and 240‐mg dose. Despite the relatively short t½s, total exercise duration and time to onset of angina and S‐T segment depression were longer than placebo values for 4 hr after the 120‐mg dose and for 8 hr after the 240‐mg dose. Percentage increase in treadmill time and log of plasma verapamil levels correlated. All patients with plasma levels above 100 ng/ml had at least a 50% increase in exercise duration. Thus measurement of plasma verapamil levels are useful in patients who fail to respond to a dose of verapamil. If the level is below 100 ng/ml, increasing the dose of verapamil may improve response.Clinical Pharmacology and Therapeutics(1984)36,25–32; doi:1

ISSN:0009-9236    

DOI:10.1038/clpt.1984.134

年代:1984

数据来源: WILEY

摘要:

Large doses (960 to 3200 mg/day) of propranolol were taken by eight patients with chronic schizophrenia in a double‐blind therapeutic trial. To investigate the effects of such treatment on central monoaminergic processes, samples of cerebrospinal fluid (CSF) were drawn before starting the study and after 31 to 63 days (X̄=49 days) on propranolol. Concentrations in CSF of 3‐methoxy‐4‐hydroxyphenylglycol (MHPG), 5‐hydroxyindoleacetic acid (5‐HIAA), and homovanillic acid (HVA), the principal metabolites of norepinephrine, serotonin, and dopamine, were determined by HPLC with electrochemical detection. The level of HVA did not change. CSF 5‐HIAA levels decreased an average of 34%, which indicates reduced turnover of serotonin in the central nervous system (CNS). There was a strong correlation between duration of treatment with propranolol and change in CSF 5‐HIAA levels. The concentration of MHPG in CSF increased an average of 39%; this could have resulted from increased turnover of CNS norepinephrine as a consequence of the blockade of central β‐adrenoceptors or of altered metabolism and clearance of peripheral MHPG. Psychotic symptoms of the patients, as indicated by the 3‐day average score on the Bunney‐Hamburg scale, were not affected by treatment.Clinical Pharmacology and Therapeutics(1984)36,33–39;

ISSN:0009-9236    

DOI:10.1038/clpt.1984.135

年代:1984

数据来源: WILEY

摘要:

The hemodynamic dose‐response effects of intravenous acebutolol, a cardioselective β‐adrenoceptor antagonist with intrinsic sympathomimetic activity, were evaluated in 12 male subjects with angiographically confirmed coronary artery disease. At rest after a saline solution control period, four doubling intravenous boluses of acebutolol (logarithmic cumulative dosage of 20, 40, 80, and 160 mg) were injected at 4‐min intervals; hemodynamic variables were recorded 2 to 4 min after each injection. Hemodynamic effects of the drug during steady‐state exercise were evaluated by comparison of a control exercise period with observations made at the same workload (25W to 50W) after the maximum cumulative dose (160 mg). After the four intravenous boluses, plasma acebutolol concentrations rose in log‐linear fashion and levels achieved (0.6 to 3.5 µ/ml) were within the range at which substantial pharmacodynamic activity is usually present (i.e., 0.02 to 0.2 µ/ml). Compared with control measurements at rest after saline solution injection, these plasma concentrations of acebutolol resulted in a quadratic reduction in heart rate (maximum ΔHR, −4 bpm) and a linear increase in pulmonary artery occluded pressure (maximum ΔPAOP, +3 mm Hg) without change in systemic arterial pressure. There was a small reduction in cardiac output (Δ cardiac index [CI], −0.2 l/min/m2). During steady‐state supine bicycle exercise, there were significant reductions in systolic blood pressure (ΔSBP, −15 mm Hg, or 9%) HR (−9 bpm or −9%), cardiac output (ΔCI, −1.0 l/min/m2, or −18%), and increase in PAOP (+8 mm Hg, or +38%). The relatively small changes induced in resting hemodynamic variables over a wide intravenous dose range of acebutolol demonstrated its relative hemodynamic safety in severe coronary artery disease. Relief of exercise‐induced angina was achieved at the cost of a relatively modest depression of left ventricular function.Clinical Pharmacology and Therapeutics(1984

ISSN:0009-9236    

DOI:10.1038/clpt.1984.136

年代:1984

数据来源: WILEY

摘要:

The specific airway conductance (sGaw) response of eight normal men to inhaled salbutamol, 200, 600, and 1800 µg, was measured on 3 separate days. On each occasion subjects received either placebo, long‐acting propranolol (160 mg), or penbutolol (40 mg) orally in a double‐blind manner after baseline lung function determination. After placebo, mean sGaw rose from a baseline of 2.07±0.15 to 2.81±0.25 kPa−1· sec−1after 200 µg salbutamol. There was little further airway dilation with higher doses of salbutamol. With long‐acting propranolol, there was no significant airway dilation after 200 µg salbutamol but there was after 600 and 1800 µg inhaled salbutamol; baseline sGaw rose from 2.02±0.17 to 2.70±0.28 and 2.95±0.32 kPa−1· sec−1. Penbutolol prevented any significant airway dilation with all doses of salbutamol. Penbutolol at the doses used appears to be a more potent blocker of β2‐receptors than does propranolol.Clinical Pharmacology and Therapeutics(1984)36,47

ISSN:0009-9236    

DOI:10.1038/clpt.1984.137

年代:1984

数据来源: WILEY

摘要:

The ability to hydroxylate debrisoquine is known to be polymorphically distributed, with about 8% to 9% of the North American Caucasian population being poor metabolizers. We have shown that the ability to 4‐hydroxylate propranolol is also polymorphically determined and that it cosegregates with ability to metabolize debrisoquine, such that poor debrisoquine metabolizers produce much less 4‐hydroxypropranolol (4‐OH propranolol) than do extensive metabolizers. There was no significant difference, however, between plasma propranolol concentrations after either single or multiple doses in the two groups. Despite the substantial difference in production of the pharmacologically active 4‐OH metabolite, no difference was seen in the extent of β‐blockade induced in the extensive and poor metabolizers, which implies that 4‐OH propranolol does not contribute substantially to β‐blockade.Clinical Pharmacology and Therapeutics(1984)36,51–56; doi:10.

ISSN:0009-9236    

DOI:10.1038/clpt.1984.138

年代:1984

数据来源: WILEY