摘要:

α‐Adrenoceptor blockade after placebo and 5‐mg oral doses of prazosin was assessed in five normal subjects over a range of phenylephrine infusion rates. Systolic blood pressure during a 400‐µg/min infusion of phenylephrine at 3 hr after placebo or prazosin was 172.8 ± 6.2 and 108.7 ±4.4 mm Hg (p<0.05). The phenylephrine effects were blocked from 1 hr to at least 7 hr after prazosin. The drug‐sensitivity ratio, an indicator of α‐adrenoceptor blockade, before prazosin was 1.1, rising to 4 at 1 hr, 4.9 at 3 hr, 5.7 at 5 hr, and 4 at 7 hr after oral prazosin. The highest prazosin plasma concentration after a 5‐mg oral dose was 29.3 ± 6.6 ng/ml. It occurred 1 hr after prazosin. The elimination half‐life was 2.9 ± 0.3 hr. After oral prazosin the α‐adrenoceptor blockade response did not correlate with prazosin plasma concentration.Clinical Pharmacology and Therapeutics(1981)29,143–148

ISSN:0009-9236    

DOI:10.1038/clpt.1981.23

年代:1981

数据来源: WILEY

摘要:

We assessed the effects of acebutolol, a cardioselective beta blocker, on global and regional left ventricular function in 26 patients with chronic angina pectoris. All patients underwent rest and maximal supine bicycle exercise radionuclide angiography while on placebo and oral acebutolol (400 mg three times a day). Resting ejection fraction on placebo was 51 ± 3% and on acebutolol was 54 ± 3% (p<0.05). No resting ejection fraction decreased ≥7%. Only one patient (resting ejection fraction 28% on placebo and 21% on acebutolol) developed signs of fluid retention. Exercise nuclear studies on placebo revealed responses consistent with coronary artery disease (abnormal ejection fraction response to exercise and regional wall motion abnormalities) in 24 of 26 patients. Peak exercise ejection fraction was of the same order on placebo and acebutolol (51 ± 3% and 54 ± 3%, p = NS). In four patients the ejection fraction response to exercise became normal and in five patients all regional wall motion abnormalities became normal on acebutolol. Cardioselective beta blockade with acebutolol in effective antianginal doses is safe and may improve resting and exercise ventricular function.Clinical Pharmacology and Therapeutics(1981)29,149–154; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1981.24

年代:1981

数据来源: WILEY

摘要:

Eight patients who improved their exercise duration to angina or marked fatigue (≥25%) on timolol 10 to 30 mg twice daily over that on placebo 8 to 14 mo previously were subjects in a double‐blind, randomized, crossover 4‐wk study of the effect of timolol on exercise duration 2 and 12 hr after medication. One patient was discontinued from the study because unstable angina developed on placebo. Mean exercise duration on timolol over control was increased at 12 hr (p<0.02) and at 2 hr (p<0.001) after drug. There was an increase in exercise duration ≥25% on timolol over control compared with placebo in three of seven patients (43%) 12 hr after drug and in seven of seven (100%) 2 hr after drug. Timolol 10 to 30 mg twice daily prolongs exercise duration to angina or marked fatigue at 2 hr after drug and in some responders at 12 hr after drug.Clinical Pharmacology and Therapeutics(1981)29,155–159; doi:10.1038/cl

ISSN:0009-9236    

DOI:10.1038/clpt.1981.25

年代:1981

数据来源: WILEY

摘要:

Although extensive evidence obtained in animals and in vitro supports the existence of an α‐receptor‐mediated inhibitory regulation of norepinephrine release, the importance of such a system in man is not established. Norepinephrine release was physiologically stimulated by change of posture and dynamic exercise in subjects while they were infused with phenylephrine, a predominant α1‐receptor agonist, α‐methylnorepinephrine, a predominant α2‐agonist, and saline. Agonist infusions were administered both at rates that induced a slight elevation in supine systolic pressure and at nonpressor rates. Agonist concentrations that induced much the same pressor responses (α1) were assumed on the basis of in vitro experiments to differ substantially in their affinity for α2‐receptors. The hemodynamic response and the increase of plasma norepinephrine induced by changes in posture and exercise were of the same order during infusions of α‐methylnorepinephrine, phenylephrine, and saline. Similar results from the “nonpressor” as from “pressor” agonist infusions suggested that baroreflex‐induced reduction in sympathetic neuronal activity had not confounded the results. Correction of plasma concentrations for individual values of norepinephrine clearance provided an index of norepinephrine release into the circulation that was not changed by phenylephrine or α‐methylnorepinephrine. These results raise the question of the importance of peripheral α2‐receptors in the regulation of norepinephrine release in man.Clinical Pharmacology and Therapeutics(1981

ISSN:0009-9236    

DOI:10.1038/clpt.1981.26

年代:1981

数据来源: WILEY

摘要:

The purpose of our investigation was to determine kinetics of naproxen [(+)‐6‐methoxy‐α‐methyl‐2‐naphthaleneacetic acid] relative to its inhibition of PGF2αrelease during thromhin‐induced platelet aggregation in man after a single oral dose of 250 or 500 mg. Naproxen and its metabolite 6‐hydroxy‐α‐methyl‐2‐naphthaleneacetic acid were measured by high‐performance, reversed‐phase liquid chromatography with fiuorimetric detection. PGF2αwas measured by radioimmunoassay in platelet‐rich plasma (PRP). Our subjects were four healthy adult men and five dysmenorrheic women. Peak concentrations of naproxen varied between 26 and 69 µg/ml and half‐lifes varied between 9.5 and 21.9 hr, x̄ = 16.4 hr ± 4.4 (SD). Naproxen plasma protein binding exceeded 99.9%. The concentration of the metabolite was less than 1% of naproxen and followed the same plasma concentration profile as the parent compound. The basal concentration of PGF2αvaried between 0.13 and 6.3 ng/ml, x̄ = 1.5 ± 1.9 nglml. With no exception, there was a marked decrease in the PGF2αconcentration in thrombin‐stimulated PRP during therapy, and concentration was inversely correlated to the total plasma naproxen concentration.Clinical Pharmacology and Therapeut

ISSN:0009-9236    

DOI:10.1038/clpt.1981.27

年代:1981

数据来源: WILEY

摘要:

In a double‐blind study using patients' subjective reports as indices of analgesia, the relative analgesic potency of intramuscular and oral nalbuphine was determined in 104 postoperative patients. Effects of single doses of 3 and 9 mg of intramuscular nalbuphine were compared with those of 15‐ and 45‐mg oral doses of nalbuphine by means of a parallel study design (26 patients per treatment group). When both intensity and duration of analgesia are considered (i.e., total analgesic effect), oral nalbuphine is ¼ to ⅕ as potent as intramuscular nalbuphine. In terms of peak effect, however, oral nalbuphine is only 1/10 as potent. The oral/parenteral potency ratio for total effect is close to those obtained by Houde et al. in studies of morphine (⅙), metopon (⅕), hydromorphone (⅕), and oxymorphone (⅙) and suggests that oral nalbuphine undergoes substantial biotransformation on first pass through gut mucosa and liver. Since intramuscular nalbuphine is approximately equipotent to morphine, it should be feasible to equal the analgesia induced by the usual intramuscular doses of morphine with reasonable oral doses of nalbuphine. Although nalbuphine is a mixed agonist/antagonist analgesic, no psychotomimetic reactions were observed.Clinical Pharmacology and Therapeutics(1981)29,174–180; doi:1

ISSN:0009-9236    

DOI:10.1038/clpt.1981.28

年代:1981

数据来源: WILEY

摘要:

High‐performance liquid chromatography (HPLC) analysis was performed on methylene chloride extracts of urine from six subjects after administration of3H‐digoxin‐12α and unlabeled digoxin by nasogastric tube under four conditions: pentagastrin and control saline infusions, each in the supine and ambulatory states. There were no differences with change in position. With pentagastrin stimulation of acid secretion, there was extensive intragastric hydrolysis, mainly to digoxigenin; there was further extensive biotransformation leading to an increase in both extractable and unextractable metabolites in urine, particularly the latter. In the first 5 hr mean digoxin was only 17% and unextractable metabolites were 54% of total urine radioactivity. Extractable radioactivity was found under HPLC peaks with retention times of digoxin, digoxigenin, and its mono‐ and bis‐digitoxosides. There were also three other peaks that were not identified; two correlated with gastric H+activity and with the peak for digoxigenin, which is probably their precursor since similar peaks were found after ingestion of digoxigenin. The third unidentified peak eluted immediately after the digoxin, with which it correlated: it may have a close structural relationship to digoxin. Gastric acid stimulation induced a major increase in the production of urinary metabolites and may prove a useful model for the study of digoxin biotransformation, which is not yet well defined.Clinical Pharmacology and Therapeutics(1981)29,181–190; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1981.29

年代:1981

数据来源: WILEY

摘要:

Nine patients with compensated alcoholic and nonalcoholic cirrhosis of the liver and 11 patients with peptic ulcer received 200 mg of Cimetidine orally and intravenously. No differences were observed in Cimetidine clearance between the group with peptic ulcer (556 ± 44 ml/min, x̄ ± SEM) and the group with cirrhosis (606 ± 64 ml/ min). The bioavailability of Cimetidine was unchanged (84 ± 4% and 97 ± 7%). In the patients with cirrhosis, Cimetidine clearance did not correlate with galactose elimination capacity or antipyrine clearance. Cimetidine clearance was related to creatinine clearance only when both groups were considered. A reduction of Cimetidine dose in patients with compensated cirrhosis appears unwarranted.Clinical Pharmacology and Therapeutics(1981)29,191–197; doi:10.1038/clpt

ISSN:0009-9236    

DOI:10.1038/clpt.1981.30

年代:1981

数据来源: WILEY

摘要:

Tiotidine and Cimetidine kinetics and dynamics were compared to assess mechanisms of the longer duration of effect of tiotidine in man. Both drugs had similar lag times for absorption. Tiotidine with a meal was more slowly absorbed than when fasting and was also more slowly absorbed than Cimetidine with a meal. The elimination rates for both drugs did not differ; they were both approximately 2 to 3 hr. Oral doses of Cimetidine achieved areas under the plasma concentration curve approximately three times that of tiotidine but these concentrations were only 1/10 as potent. The Cimetidine concentration inducing 50% inhibition of food‐stimulated gastric acid secretion was 0.41 ± 0.04 whereas it was 0.04 ± 0.003 µg/ml for tiotidine. The effect of tiotidine lasted longer than that of cimetidine because the doses recommended for use in man resulted in higher concentrations in plasma relative to effective concentration than clinical doses of cimetidine.Clinical Pharmacology and Therapeutics(1981)29,198–202; doi:10.1038/clpt.

ISSN:0009-9236    

DOI:10.1038/clpt.1981.31

年代:1981

数据来源: WILEY

摘要:

Drug binding to protein is known to be altered in renal disease. Explanations include hypoproteinemia, competitive or noncompetitive inhibition, and basic functional defects in the binding protein. Albumin, the primary binding protein for phenytoin (DPH), was isolated from the plasma of patients with severe renal failure as well as from normal controls. DPH binding was not different between the albumin preparations isolated from the two sources, although some differences were detected in the apparent affinity constant and the number of binding sites. It would appear that the significant defect in DPH binding in renal disease cannot be attributed to a basic functional defect in the drug‐binding protein albumin.Clinical Pharmacology and Therapeutics(1981)29,203–210; doi:10.1038/clpt.198

ISSN:0009-9236    

DOI:10.1038/clpt.1981.32

年代:1981

数据来源: WILEY