摘要:

Each of seven subjects received on a weekly basis placebo or 10, 20, 40, 80, or 160 mg propranolol orally four times daily. The effect of propranolol on the resting heart rate and the heart rate response to the Valsalva maneuver, tilt, isoproterenol, and maximal exercise were measured. Coefficients of determination were calculated from the individual dose‐response curves. The results indicate that the resting heart rate and the tachycardiac response to the Valsalva maneuver and tilt cannot be used to estimate beta blockade. Propranolol concentrations correlated well (mean r2= 0.80) with the isoproterenol dose ratio minus one, but isoproterenol challenges appear clinically inapplicable. Reduction in maximal exercise tachycardia correlated best with propranolol concentrations (mean r2= 0.89) but, to the extent that exercise could not be performed, there was no reliable way of clinically documenting beta blockade and only the serum concentration of propranolol was available as an indicator of appropriate therapy.Clinical Pharmacology and Therapeutics(1981)30, 283–290; doi:10.1038/clpt.1981

ISSN:0009-9236    

DOI:10.1038/clpt.1981.161

年代:1981

数据来源: WILEY

摘要:

The plasma level: time profile for l‐propranolol and total propranolol concentrations were examined in normotensive subjects after intravenous and oral dl‐propranolol. l‐Propranolol concentrations in plasma accounted for about 60% of total propranolol. This was attributed to lower volume of distribution for the isomer. Mean plasma clearance of l‐propranolol was similarly affected while apparent plasma half‐life for the l‐isomer and total propranolol were of the same order. Oral bioavailability of l‐ and total propranolol averaged 40.7 ± 8.3% and 42.4 ± 12.9%. Food and hydralazine increased oral bioavailability of total and l‐propranolol by similar magnitudes. We conclude that differences in the kinetics of l‐ and total propranolol concentrations in plasma are small and probably of no clinical significance. Presystemic clearance of propranolol in man does not appear to be stereospecific.Clinical Pharmacology and Therapeutics(1981)30, 291–296; doi

ISSN:0009-9236    

DOI:10.1038/clpt.1981.162

年代:1981

数据来源: WILEY

摘要:

Our subjects were seven severely hypertensive patients with blood pressures (BPs) over 140/90 who were using minoxidil, propranolol, and diuretics. Clonidine followed by prazosin was added to their regimen on an outpatient basis to establish the dose‐response for BP and catecholamines. Plasma renin activity (PRA), body weight, and renal function were measured. Clonidine was given in doses of 0.2, 0.4, 0.6, and 0.8 mg/day. Supine and standing systolic BP decreased at all dose levels of clonidine (P<0.01, P<0.05). Diastolic BP decreased in the standing position with doses of 0.4, 0.6, and 0.8 mg (P<0.01, P<0.05). Subjects were hypernoradrenergic initially with plasma norepinephrine (PNE) 895 ± 122 pg/ml. PNE was suppressed by 0.2 to 0.8 mg clonidine (P<0.01) with near maximal suppression at 0.4 mg daily. Systolic BP correlated with PNE (r = 0.59, P<0.001). Supine and standing PRA decreased after 0.2 mg clonidine (P<0.05) but not after higher doses. Our findings suggest the antihypertensive action of clonidine is related to PNE suppression but not to that of PRA. Plasma epinephrine (PE), body weight, and renal function did not change. Prazosin was given after clonidine to the same patients in a dose range of 3 to 40 mg/day. With doses of 6 to 40 mg, systolic and diastolic and supine and standing BP fell (P<0.001, P<0.01). PNE remained elevated throughout all dose levels and did not correlate with BP. Weight rose with prazosin (P<0.02) but PE, PRA, and renal function did not change. Hence, clonidine and prazosin induced additional lowering of BP but had different effects on PNE and weight.Clinical Pharmacology and Therapeutics(1981)30, 297–302; doi:10.1038/clpt.198

ISSN:0009-9236    

DOI:10.1038/clpt.1981.163

年代:1981

数据来源: WILEY

摘要:

Six normal subjects were studied after graded bolus injections of isoproterenol. Log dose‐response curves for increases in both heart rate (mostly β1) and amplitude of physiologic tremor (β2) were constructed for each subject in the control state and 2 hr after 10 or 40 mg propranolol, 200 mg sotalol, or placebo. All heart rate curves were shifted to the right in an approximately parallel fashion by all active treatments (40 mg propranolol>200 mg sotalol>10 mg propranolol). The tremor curve was also shifted to the right by 10 mg propranolol in an approximately parallel fashion and to the same extent as the heart rate curve (both dose‐ratios = 6.1), but the tremor curves after both 40 mg propranolol and 200 mg sotalol appeared to be flattened as well as shifted laterally. We conclude that whereas it may be possible that 10 mg propranolol acts as a competitive antagonist of isoproterenol at β2‐sites in skeletal muscle, 40 mg propranolol and 200 mg sotalol must have additional actions in reducing isoproterenol tremor. The possibilities are discussed.Clinical Pharmacology and Therapeutics(1981)30, 303–310; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1981.164

年代:1981

数据来源: WILEY

摘要:

To explore a possible interaction between digoxin and verapamil, a single‐dose kinetic study of digoxin was performed and then repeated after 10 days of verapamil treatment in eight healthy subjects. Verapamil diminished the apparent central distribution volume of digoxin from 0.83 ± 0.25 to 0.64 ± 0.17 l/kg (P<0.05) and reduced total body clearance of digoxin from 3.28 ± 0.58 to 2.15 ± 0.66 ml/min/kg (P<0.001) by impairing both renal and extrarenal clearance. Biological digoxin half‐life rose from 38.6 ± 8.5 to 50.5 ± 8.3 hr (P<0.005). Reduction of renal clearance of digoxin may be due to inhibition of tubular secretion. The underlying mechanisms of extrarenal interaction are not known, but impaired hepatic degradation of digoxin induced by verapamil should be considered.Clinical Pharmacology and Therapeutics(1981)30, 311–316; doi:10.1038/c

ISSN:0009-9236    

DOI:10.1038/clpt.1981.165

年代:1981

数据来源: WILEY

摘要:

Ten normal subjects were given 0.4 mg digoxin intravenously by bolus injection over 3 to 5 min and by constant‐rate infusion for 1 hr. Urinary excretion of digoxin over the next 6 days, as measured by radioimmunoassay, was similar after both the rates of intravenous injection. In one subject, who excreted substantial amounts of digoxin reduction products, no difference was apparent in the amount of reduced metabolites excreted. These results are not in agreement with previous reports of an effect of intravenous infusion rate on urinary digoxin excretion.Clinical Pharmacology and Therapeutics(1981)30, 317–320; doi:10.1038/clpt.1981

ISSN:0009-9236    

DOI:10.1038/clpt.1981.166

年代:1981

数据来源: WILEY

摘要:

Although exercise testing is commonly used to determine the efficacy of antianginal drugs, there is little information on the effect of frequent exposure to such testing over periods as long as 6 mo. In our study 10 patients (four men and six women) with stable angina pectoris received placebo for 6 mo. Treadmill testing followed a modified Bruce protocol. All patients exercised to an end point of typical anginal pain and 1 mm or more of ST depression. The first treadmill test for diagnostic purposes was followed by testing every 2 wk for 6 mo. Sublingual nitroglycerin was permitted to abort attacks of angina. Parameters evaluated included heart rate, double product, and duration of exercise. There was no change in the maximal heart rate (x= 109 at 2 wk and 112 at 6 mo) or double product (x= 17,002 at 2 wk and 17,249 at 6 mo). On the other hand, duration increased (x7.8 min at two wk and 9.9 min at 6 mo). Thus, although treadmill testing showed reproducible measurements of maximal heart rate and double product over 6 mo, exercise duration increased progressively.Clinical Pharmacology and Therapeutics(1981)30, 321–327; doi:10.1038/clpt.1981.1

ISSN:0009-9236    

DOI:10.1038/clpt.1981.167

年代:1981

数据来源: WILEY

摘要:

Captopril was given alone and in combination with diuretics to 49 patients with hypertension for 1 to 12 mo. Within 2 mo blood pressure reduction correlated with pretreatment plasma renin activity and response to the infusion of angiotensin II antagonist, but these effects were not present at 4 mo. Plasma and urinary aldosterone were suppressed but serum converting enzyme activity, plasma bradykinin, kallikrein, and prostaglandins (E and F) were in the normal range throughout the study period. Indomethacin (150 mg/day) for 1 wk abolished the hypotensive effect of captopril. Despite sustained reduction of blood pressure, plasma catecholamines were not elevated and urinary catecholamines were suppressed in patients on captopril alone. It is concluded that another mechanism, such as enhancement of renal or local kinin‐prostaglandin system, as well as suppression of the renin‐angiotensin‐aldosterone system may be involved in the long‐term efficacy of captopril. Sympathetic activity may also be depressed and contribute to the hypotensive effect.Clinical Pharmacology and Therapeutics(1981)30, 328–335; doi:10.1038/clp

ISSN:0009-9236    

DOI:10.1038/clpt.1981.168

年代:1981

数据来源: WILEY

摘要:

The effects on the quantitative EEG and behavior of two doses (0.1 and 0.3 mg) of the novel sedative compound brotizolam were compared to those of 10 mg flurazepam and placebo in a crossover study in 11 normal men. The effects of 0.1 mg brotizolam were equivalent in intensity and duration to those of 10 mg flurazepam, while the 0.3‐mg dose of brotizolam was approximately three times as active. The relative physiologic equivalence of doses of brotizolam and flurazepam is 1 to 100. In its EEG profile, brotizolam is classified as a hypnotic‐sedative substance. Its suggested use is as a substitute for established benzodiazepines that have hypnotic, sedative, and anticonvulsant activities.Clinical Pharmacology and Therapeutics(1981)30, 336–342; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1981.169

年代:1981

数据来源: WILEY

摘要:

Six slow acetylators (SAs) and six rapid acetylators (RAs), as determined by sulfamethazine (SMZ) phenotyping, were each given a 2‐mg oral dose of clonazepam. Ninety‐six‐hour urine collections from these subjects were analyzed for clonazepam, 7‐amino clonazepam (7‐AM, clonazepam nitroreduced metabolite), and 7‐acetamido clonzepam (7‐ACT,N‐acetylated 7‐AM). The SA group excreted more 7‐AM and less 7‐ACT than the RA group; mean (±SD) recovered as 7‐AM was 22.7 ± 5.0% for the SA group and 13.6 ± 4.1% for the RA group and mean (±SD) recovered as 7‐ACT was 1.5 ± 0.4% for the SA group and 3.9 ± 1.8% for the RA group. Both differences were substantial (p<0.02 by unpaired t test) and indicate that the rate of acetylation of 7‐AM to 7‐ACT in the biotransformation of clonazepam is determined by the acetylator phenotype.Clinical Pharmacology and Therapeutics(1981)30

ISSN:0009-9236    

DOI:10.1038/clpt.1981.170

年代:1981

数据来源: WILEY